Oligonucleotides for inducing paternal UBE3A expression

- Hoffmann-La Roche Inc.

The present invention relates to oligonucleotides that are capable of inducing expression of ubiquitin-protein ligase E3A (UBE3A) from the paternal allele in animal or human neurons. The oligonucleotides target the suppressor of the UBE3A paternal allele by hybridization to SNHG14 long non-coding RNA downstream of SNORD1091B. The present invention further relates to pharmaceutical compositions and methods for treatment of Angelman syndrome.

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Description
CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 17/581,089, filed Jan. 21, 2022, which is a continuation of application Ser. No. 16/933,445, filed Jul. 20, 2020, which is a continuation of application Ser. No. 16/663,024, filed Oct. 24, 2019, which is a continuation of application Ser. No. 16/388,714, filed Apr. 18, 2019, which is a continuation of application Ser. No. 15/351,113, filed Nov. 14, 2016, which is a continuation of PCT/EP2016/077383, filed Nov. 11, 2016, which claims priority to EP15194367.7, filed Nov. 12, 2015 and EP16189502.4, filed Sep. 19, 2016, the contents of which are hereby incorporated by reference.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on Mar. 29, 2023, is named Sequence_Listing_P118867USBMMM and is 1,508,023 bytes in size.

FIELD OF INVENTION

The present invention relates to oligonucleotides (oligomers) that are complementary to and hybridize to SNHG14 downstream of SNORD109B, leading to induction of paternal expression of Ubiquitin-protein ligase E3A (UBE3A) in an animal or human. The present invention further relates to pharmaceutical compositions and methods for treatment of Angelman syndrome.

BACKGROUND

Angelman syndrome is neuro-genetic disorder caused by deletion or inactivation of the UBE3A genes on the maternally inherited chromosome 15q11.2. The paternal copy of the UBE3A gene is subject to genomic imprinting and silencing in neurons by an endogenous antisense transcript of UBE3A, termed SNHG14 (also known as UBE3A-ATS) (Meng et al. 2012 Hum Mol Genet. Vol. 21 pp. 3001-12). Other cell types than neurons seem to express the UBE3A gene from both the maternal and paternal allele.

Angelman syndrome is characterized by severe intellectual and developmental disability, sleep disturbance, seizures, jerky movements, EEG abnormalities, frequent laughter or smiling, and profound language impairments.

WO 2012/064806 discloses a method of inducing UBE3A expression in a cell by using a topoisomerase inhibitor. The method can be used to treat Angelman syndrome. There is no disclosure of antisense oligonucleotides.

WO 2014/004572 discloses oligonucleotides with 2′-O-methoxyethyl-RNA (MOE) modifications targeting mouse UBE3A-ATS. The oligonucleotides are only tested in mice related assays. In the region downstream of MBII-52 snoRNA (also known as SNORD115) and upstream of the UBE3A pre-mRNA there is no conservation between mouse and human. Oligonucleotides targeting mouse UBE3A-ATS can therefore not be translated into oligonucleotides that will function in a human. There is no disclosure of oligonucleotides targeting human UBE3A-ATS.

OBJECTIVE OF THE INVENTION

The present invention identifies novel oligonucleotides which induce human paternal UBE3A expression in neuronal without affection expression of the paternal SNORD115, SNORD116 and SNRPN transcripts significantly.

SUMMARY OF INVENTION

The present invention relates to oligonucleotides targeting a nucleic acid capable of suppressing the expression of UBE3A and to treat or prevent diseases related to decreased activity of UBE3A, in particular in neuronal cells.

Accordingly, in a first aspect the invention provides oligonucleotides which comprise a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 98% complementarity to the part of human SNHG14 long non-coding RNA corresponding to position 25278410 to 25419462 on human chromosome 15 version GRCh38.p2. This region is also resembled by SEQ ID NO: 1. The oligonucleotide can be an antisense oligonucleotide, preferably with a gapmer design. Preferably, the oligonucleotide is capable of inducing the expression of UBE3A, in particular paternal UBE3A expression in a neuron, by degradation, reduction or removal of the UBE3A suppressor, in particular by reduction of the SNHG14 long non-coding RNA transcript downstream of SNORD109B. The UBE3A re-expression is achieved, without significantly affecting the expression of SNORD115. The degradation of the target nucleic acid is preferably achieved via nuclease recruitment.

In a further aspect, the invention provides pharmaceutical compositions comprising the oligonucleotides of the invention and pharmaceutically acceptable diluents, carriers, salts and/or adjuvants.

In a further aspect, the invention provides methods for in vivo or in vitro induction of UBE3A expression in a target cell where expression of paternal UBE3A is suppressed, by administering an oligonucleotide or composition of the invention in an effective amount to said cell.

In a further aspect the invention provides methods for treating or preventing a disease, disorder or dysfunction associated with in vivo activity of UBE3A comprising administering a therapeutically or prophylactically effective amount of the oligonucleotide of the invention to a subject suffering from or susceptible to the disease, disorder or dysfunction.

In a further aspect the oligonucleotide or composition of the invention is used for the treatment or prevention of Angelman syndrome.

BRIEF DESCRIPTION OF FIGURES

FIG. 1: The upper strand illustrates the region of the SNHG14 transcript downstream of SNORD109B (UBE3A-ATS) where the black boxes indicate the location of the tested mouse oligonucleotides. The lower strand illustrates the UBE3A coding region, where the black boxes indicate exons. Exon 1 is located around 160 kb. The oligonucleotides are placed in the antisense region of Exon 9 (positioned at ˜97 kb), Exon 10 (positioned at ˜92 kb), Exon 13 (positioned at ˜77 kb) and the 5′ end of Exon 16 (positioned at ˜60 kb).

FIG. 2: Representation of the ability of the oligonucleotides, tested in Example 2, to induce re-expression of UBE3A in human neuronal cell cultures. Oligonucleotides complementary to the region of human SNHG14 long non-coding RNA between SNORD109B and the region upstream of the UBE3A coding region (position 1 to 55318 of SEQ ID NO: 1) are indicated with ● nonoverlap. Oligonucleotides complementary to the region of human SNHG14 long non-coding RNA which is antisense to the UBE3A pre-mRNA (position 55319 to 141053 of SEQ ID NO: 1) are indicated with ▴ overlap. Oligonucleotides from Table 3 with conservation to human and rhesus monkey are indicated at the bottom of each plot as ▭. Conservation between human:rhesus:mouse is indicated by ▬. The oligonucleotide concentrations were 0.2, 1 and 5 microM as indicated in the right hand side each plot.

 DEFINITIONS

Oligonucleotide

The term “oligonucleotide” as used herein is defined as it is generally understood by the skilled person as a molecule comprising two or more covalently linked nucleosides. Such covalently bound nucleosides may also be referred to as nucleic acid molecules or oligomers. Oligonucleotides are commonly made in the laboratory by solid-phase chemical synthesis followed by purification. When referring to a sequence of the oligonucleotide, reference is made to the sequence or order of nucleobase moieties, or modifications thereof, of the covalently linked nucleotides or nucleosides. The oligonucleotide of the invention is man-made, and is chemically synthesized, and is typically purified or isolated. The oligonucleotide of the invention may comprise one or more modified nucleosides or nucleotides.

Antisense Oligonucleotides

The term “Antisense oligonucleotide” as used herein is defined as oligonucleotides capable of modulating expression of a target gene by hybridizing to a target nucleic acid, in particular to a contiguous sequence on a target nucleic acid. The antisense oligonucleotides are not essentially double stranded and are therefore not siRNAs. Preferably, the antisense oligonucleotides of the present invention are single stranded.

Contiguous Nucleotide Sequence

The term “contiguous nucleotide sequence” refers to the region of the oligonucleotide which is complementary to the target nucleic acid. The term is used interchangeably herein with the term “contiguous nucleobase sequence” and the term “oligonucleotide motif sequence”. In some embodiments all the nucleotides of the oligonucleotide are present in the contiguous nucleotide sequence. In some embodiments the oligonucleotide comprises the contiguous nucleotide sequence and may, optionally comprise further nucleotide(s), for example a nucleotide linker region which may be used to attach a functional group to the contiguous nucleotide sequence. The nucleotide linker region may or may not be complementary to the target nucleic acid.

Nucleotides

Nucleotides are the building blocks of oligonucleotides and polynucleotides, and for the purposes of the present invention include both naturally occurring and non-naturally occurring nucleotides. In nature, nucleotides, such as DNA and RNA nucleotides comprise a ribose sugar moiety, a nucleobase moiety and one or more phosphate groups (which is absent in nucleosides). Nucleosides and nucleotides may also interchangeably be referred to as “units” or “monomers”.

Modified Nucleoside

The term “modified nucleoside” or “nucleoside modification” as used herein refers to nucleosides modified as compared to the equivalent DNA or RNA nucleoside by the introduction of one or more modifications of the sugar moiety or the (nucleo)base moiety. In a preferred embodiment the modified nucleoside comprises a modified sugar moiety. The term modified nucleoside may also be used herein interchangeably with the term “nucleoside analogue” or modified “units” or modified “monomers”.

Modified Internucleoside Linkage

The term “modified internucleoside linkage” is defined as generally understood by the skilled person as linkages other than phosphodiester (PO) linkages, that covalently couples two nucleosides together. Nucleotides with modified internucleoside linkage are also termed “modified nucleotides”. In some embodiments, the modified internucleoside linkage increases the nuclease resistance of the oligonucleotide compared to a phosphodiester linkage. For naturally occurring oligonucleotides, the internucleoside linkage includes phosphate groups creating a phosphodiester bond between adjacent nucleosides. Modified internucleoside linkages are particularly useful in stabilizing oligonucleotides for in vivo use, and may serve to protect against nuclease cleavage at regions of DNA or RNA nucleosides in the oligonucleotide of the invention, for example within the gap region of a gapmer oligonucleotide, as well as in regions of modified nucleosides.

In an embodiment, the oligonucleotide comprises one or more internucleoside linkages modified from the natural phosphodiester to a linkage that is for example more resistant to nuclease attack. Nuclease resistance may be determined by incubating the oligonucleotide in blood serum or by using a nuclease resistance assay (e.g. snake venom phosphodiesterase (SVPD)), both are well known in the art. Internucleoside linkages which are capable of enhancing the nuclease resistance of an oligonucleotide are referred to as nuclease resistant internucleoside linkages. In preferred embodiments at least 50% of the internucleoside linkages in the oligonucleotide, or contiguous nucleotide sequence thereof, are modified, such as at least 60%, such as at least 70%, such as at least 80 or such as at least 90% of the internucleoside linkages in the oligonucleotide, or contiguous nucleotide sequence thereof, are modified. In some embodiments all of the internucleoside linkages of the oligonucleotide, or contiguous nucleotide sequence thereof, are modified. It will be recognized that, in some embodiments the nucleosides which link the oligonucleotide of the invention to a non-nucleotide functional group, such as a conjugate, may be phosphodiester. In some embodiments all of the internucleoside linkages of the oligonucleotide, or contiguous nucleotide sequence thereof, are nuclease resistant internucleoside linkages.

Modified internucleoside linkages may be selected from the group comprising phosphorothioate, diphosphorothioate and boranophosphate. In preferred embodiments, the modified internucleoside linkages are compatible with the RNaseH recruitment of the oligonucleotide of the invention, for example phosphorothioate, diphosphorothioate or boranophosphate.

In some embodiments the internucleoside linkage comprises sulphur (S), such as a phosphorothioate internucleoside linkage.

A phosphorothioate internucleoside linkage is particularly useful due to nuclease resistance, beneficial pharmakokinetics and ease of manufacture. In preferred embodiments at least 50% of the internucleoside linkages in the oligonucleotide, or contiguous nucleotide sequence thereof, are phosphorothioate, such as at least 60%, such as at least 70%, such as at least 80 or such as at least 90% of the internucleoside linkages in the oligonucleotide, or contiguous nucleotide sequence thereof, are phosphorothioate. In some embodiments all of the internucleoside linkages of the oligonucleotide, or contiguous nucleotide sequence thereof, are phosphorothioate.

In some embodiments, the oligonucleotide comprises one or more neutral internucleoside linkage, particularly a internucleoside linkage selected from phosphotriester, methylphosphonate, MMI, amide-3, formacetal or thioformacetal.

Further internucleoside linkages are disclosed in WO2009/124238 (incorporated herein by reference). In an embodiment the internucleoside linkage is selected from linkers disclosed in WO2007/031091 (incorporated herein by reference). Particularly, the internucleoside linkage may be selected from —O—P(O)2—O—, —O—P(O,S)—O—, —O—P(S)2—O—, —S—P(O)2—O—, —S—P(O,S)—O—, —S—P(S)2—O—, —O—P(O)2—S—, —O—P(O,S)—S—, —S—P(O)2—S—, —O—PO(RH)—O—, O—PO(OCH3)—O—, —O—PO(NRH)—O—, —O—PO(OCH2CH2S—R)—O—, —O—PO(BH3)—O—, —O—PO(NHRH)—O—, —O—P(O)2—NRH—, —NRH—P(O)2—O—, —NRH—CO—O—, —NRH—CO—NRH—, and/or the internucleoside linker may be selected form the group consisting of: —O—CO—O—, —O—CO—NRH—, —NRH—CO—CH2—, —O—CH2—CO—NRH—, —O—CH2—CH2—NRH—, —CO—NRH—CH2—, —CH2—NRHCO—, —O—CH2—CH2—S—, —S—CH2—CH2—O—, —S—CH2—CH2—S—, —CH2—SO2—CH2—, —CH2—CO—NRH—, —O—CH2—CH2—NRH—CO—, —CH2—NCH3—O—CH2—, where RH is selected from hydrogen and C1-4-alkyl.

Nuclease resistant linkages, such as phosphothioate linkages, are particularly useful in oligonucleotide regions capable of recruiting nuclease when forming a duplex with the target nucleic acid, such as region G for gapmers, or the non-modified nucleoside region of headmers and tailmers. Phosphorothioate linkages may, however, also be useful in non-nuclease recruiting regions and/or affinity enhancing regions such as regions F and F′ for gapmers, or the modified nucleoside region of headmers and tailmers.

Each of the design regions may however comprise internucleoside linkages other than phosphorothioate, such as phosphodiester linkages, in particularly in regions where modified nucleosides, such as LNA, protect the linkage against nuclease degradation. Inclusion of phosphodiester linkages, such as one or two linkages, particularly between or adjacent to modified nucleoside units (typically in the non-nuclease recruiting regions) can modify the bioavailability and/or bio-distribution of an oligonucleotide—see WO2008/113832, incorporated herein by reference.

In an embodiment all the internucleoside linkages in the oligonucleotide are phosphorothioate and/or boranophosphate linkages. Preferably, all the internucleoside linkages in the oligonucleotide are phosphorothioate linkages.

Nucleobase

The term nucleobase includes the purine (e.g. adenine and guanine) and pyrimidine (e.g. uracil, thymine and cytosine) moiety present in nucleosides and nucleotides which form hydrogen bonds in nucleic acid hybridization. In the context of the present invention the term nucleobase also encompasses modified nucleobases which may differ from naturally occurring nucleobases, but are functional during nucleic acid hybridization. In this context “nucleobase” refers to both naturally occurring nucleobases such as adenine, guanine, cytosine, thymidine, uracil, xanthine and hypoxanthine, as well as non-naturally occurring variants. Such variants are for example described in Hirao et al (2012) Accounts of Chemical Research vol 45 page 2055 and Bergstrom (2009) Current Protocols in Nucleic Acid Chemistry Suppl. 37 1.4.1.

In a some embodiments the nucleobase moiety is modified by changing the purine or pyrimidine into a modified purine or pyrimidine, such as substituted purine or substituted pyrimidine, such as a nucleobased selected from isocytosine, pseudoisocytosine, 5-methyl cytosine, 5-thiozolo-cytosine, 5-propynyl-cytosine, 5-propynyl-uracil, 5-bromouracil 5-thiazolo-uracil, 2-thio-uracil, 2′thio-thymine, inosine, diaminopurine, 6-aminopurine, 2-aminopurine, 2,6-diaminopurine and 2-chloro-6-aminopurine.

The nucleobase moieties may be indicated by the letter code for each corresponding nucleobase, e.g. A, T, G, C or U, wherein each letter may optionally include modified nucleobases of equivalent function. For example, in the exemplified oligonucleotides, the nucleobase moieties are selected from A, T, G, C, and 5-methyl cytosine. Optionally, for LNA gapmers, 5-methyl cytosine LNA nucleosides may be used.

Modified Oligonucleotide

The term modified oligonucleotide describes an oligonucleotide comprising one or more sugar-modified nucleosides and/or modified internucleoside linkages. The term chimeric” oligonucleotide is a term that has been used in the literature to describe oligonucleotides with modified nucleosides.

Complementarity

The term complementarity describes the capacity for Watson-Crick base-pairing of nucleosides/nucleotides. Watson-Crick base pairs are guanine (G)-cytosine (C) and adenine (A) -thymine (T)/uracil (U). It will be understood that oligonucleotides may comprise nucleosides with modified nucleobases, for example 5-methyl cytosine is often used in place of cytosine, and as such the term complementarity encompasses Watson Crick base-paring between non-modified and modified nucleobases (see for example Hirao et al (2012) Accounts of Chemical Research vol 45 page 2055 and Bergstrom (2009) Current Protocols in Nucleic Acid Chemistry Suppl. 37 1.4.1).

The term “% complementary” as used herein, refers to the number of nucleotides in percent of a contiguous nucleotide sequence in a nucleic acid molecule (e.g. oligonucleotide) which, at a given position, are complementary to (i.e. form Watson Crick base pairs with) a contiguous nucleotide sequence, at a given position of a separate nucleic acid molecule (e.g. the target nucleic acid). The percentage is calculated by counting the number of aligned bases that form pairs between the two sequences, dividing by the total number of nucleotides in the oligonucleotide and multiplying by 100. In such a comparison a nucleobase/nucleotide which does not align (form a base pair) is termed a mismatch.

The term “fully complementary”, refers to 100% complementarity.

Hybridization

The term “hybridizing” or “hybridizes” as used herein is to be understood as two nucleic acid strands (e.g. an oligonucleotide and a target nucleic acid) forming hydrogen bonds between base pairs on opposite strands thereby forming a duplex. The affinity of the binding between two nucleic acid strands is the strength of the hybridization. It is often described in terms of the melting temperature (Tm) defined as the temperature at which half of the oligonucleotides are duplexed with the target nucleic acid. At physiological conditions Tm is not strictly proportional to the affinity (Mergny and Lacroix, 2003, Oligonucleotides 13:515-537). The standard state Gibbs free energy ΔG° is a more accurate representation of binding affinity and is related to the dissociation constant (Kd) of the reaction by ΔG°=−RTIn(Kd), where R is the gas constant and T is the absolute temperature. Therefore, a very low ΔG° of the reaction between an oligonucleotide and the target nucleic acid reflects a strong hybridization between the oligonucleotide and target nucleic acid. ΔG° is the energy associated with a reaction where aqueous concentrations are 1 M, the pH is 7, and the temperature is 37° C. The hybridization of oligonucleotides to a target nucleic acid is a spontaneous reaction and for spontaneous reactions ΔG° is less than zero. ΔG° can be measured experimentally, for example, by use of the isothermal titration calorimetry (ITC) method as described in Hansen et al., 1965, Chem. Comm. 36-38 and Holdgate et al., 2005, Drug Discov Today. The skilled person will know that commercial equipment is available for ΔG° measurements. ΔG° can also be estimated numerically by using the nearest neighbor model as described by SantaLucia, 1998, Proc Natl Acad Sci USA. 95: 1460-1465 using appropriately derived thermodynamic parameters described by Sugimoto et al., 1995, Biochemistry 34:11211-11216 and McTigue et al., 2004, Biochemistry 43:5388-5405. In order to have the possibility of modulating its intended nucleic acid target by hybridization, oligonucleotides of the present invention hybridize to a target nucleic acid with estimated ΔG° values below −10 kcal for oligonucleotides that are 10-30 nucleotides in length. In some embodiments the degree or strength of hybridization is measured by the standard state Gibbs free energy ΔG°. The oligonucleotides may hybridize to a target nucleic acid with estimated ΔG° values below the range of −10 kcal, such as below −15 kcal, such as below −20 kcal and such as below −25 kcal for oligonucleotides that are 8-30 nucleotides in length. In some embodiments the oligonucleotides hybridize to a target nucleic acid with an estimated ΔG° value of −10 to −60 kcal, such as −12 to −40, such as from −15 to −30 kcal or −16 to −27 kcal such as −18 to −25 kcal.

The Target

The target refers to the protein which it is desired to modulate.

Target Nucleic Acid

A target nucleic acid is the intended target which the oligonucleotide of the invention hybridizes to, and may for example be a gene, a RNA, a non-coding RNA, a long non-coding RNA, a mRNA, and pre-mRNA, a mature mRNA or a cDNA sequence. In some embodiments the target nucleic acid is a non-coding RNA or a long non-coding RNA, or a subsequence thereof. For in vivo or in vitro application, the oligonucleotide of the invention is capable of decreasing the level of the SNHG14 transcript downstream of SNORD109B of and thereby relieving the suppression of the paternal UBE3A transcript in the intended target cell. The contiguous sequence of nucleobases of the oligonucleotide of the invention is complementary to the target nucleic acid, as measured across the length of the oligonucleotide, optionally with the exception of one or two mismatches, and optionally excluding nucleotide based linker regions which may link the oligonucleotide to an optional functional group such as a conjugate.

Target Sequence

The oligonucleotide comprises a contiguous nucleotide sequence which is complementary to or hybridizes to a sub-sequence of the target nucleic acid molecule. The term “target sequence” as used herein refers to a sequence of nucleotides present in the target nucleic acid which comprises the nucleobase sequence which is complementary to the oligonucleotide of the invention. In some embodiments, the target sequence consists of a region on the target nucleic acid which is complementary to the contiguous nucleotide sequence of the oligonucleotide of the invention. In some embodiments the target sequence is longer than the complementary sequence of a single oligonucleotide, and may, for example represent a preferred region of the target nucleic acid which may be targeted by several oligonucleotides of the invention.

The oligonucleotide of the invention comprises a contiguous nucleotide sequence which is complementary to the target nucleic acid, such as a target sequence.

The oligonucleotide comprises a contiguous nucleotide sequence of at least 8 nucleotides which is complementary to or hybridizes to a target sequence present in the target nucleic acid molecule. The contiguous nucleotide sequence (and therefore the target sequence) comprises of at least 8 contiguous nucleotides, such as 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 contiguous nucleotides, such as from 12-25, such as from 14-18 contiguous nucleotides.

Target Cell

The term a target cell as used herein refers to a cell which is expressing the target nucleic acid. In some embodiments the target cell may be in vivo or in vitro. In some embodiments the target cell is a mammalian cell such as a rodent cell, such as a mouse cell or a rat cell, or a primate cell such as a monkey cell or a human cell. In preferred embodiments the target cell is a neuronal cell.

Naturally Occurring Variant

The term “naturally occurring variant” refers to variants of SNHG14 transcript downstream of SNORD109B gene or transcripts which originate from the same genetic loci as the target nucleic acid, but may differ for example, by virtue of degeneracy of the genetic code causing a multiplicity of codons in the long non-coding RNA. The oligonucleotide of the invention may therefore be designed to target the target nucleic acid and naturally occurring variants thereof.

Modulation of Expression

The term “modulation of expression” as used herein is to be understood as an overall term for an oligonucleotide's ability to alter the amount of UBE3A protein when compared to the amount of UBE3A before administration of the oligonucleotide. Alternatively modulation of expression may be determined by reference to a control experiment where the oligonucleotide of the invention is not administered. The modulation effected by the oligonucleotide is related to it's ability to reduce, remove, prevent, lessen, lower or terminate the suppression of the paternal UBE3A transcript, e.g. by degradation or removal of the non-coding SNHG14 transcript downstream of SNORD109B or by blockage or prevention of polymerase activity associated with the SNHG14 transcript downstream of SNORD109B. The modulation can also be viewed as the oligonucleotide's ability to restore, increase or enhance expression of paternal UBE3A, e.g. by removal or blockage of inhibitory mechanisms affected by the non-coding SNHG14 transcript downstream of SNORD109B.

High Affinity Modified Nucleosides

A high affinity modified nucleoside is a modified nucleotide which, when incorporated into the oligonucleotide enhances the affinity of the oligonucleotide for its complementary target, for example as measured by the melting temperature (Tm). A high affinity modified nucleoside of the present invention preferably result in an increase in melting temperature between +0.5 to +12° C., more preferably between +1.5 to +10° C. and most preferably between +3 to +8° C. per modified nucleoside. Numerous high affinity modified nucleosides are known in the art and include for example, many 2′ substituted nucleosides as well as locked nucleic acids (LNA) (see e.g. Freier & Altmann; Nucl. Acid Res., 1997, 25, 4429-4443 and Uhlmann; Curr. Opinion in Drug Development, 2000, 3(2), 293-213).

Sugar Modifications

The oligomer of the invention may comprise one or more nucleosides which have a modified sugar moiety, i.e. a modification of the sugar moiety when compared to the ribose sugar moiety found in DNA and RNA.

Numerous nucleosides with modification of the ribose sugar moiety have been made, primarily with the aim of improving certain properties of oligonucleotides, such as affinity and/or nuclease resistance.

Such modifications include those where the ribose ring structure is modified, e.g. by replacement with a hexose ring (HNA), or a bicyclic ring, which typically have a biradicle bridge between the C2 and C4 carbons on the ribose ring (LNA), or an unlinked ribose ring which typically lacks a bond between the C2 and C3 carbons (e.g. UNA). Other sugar modified nucleosides include, for example, bicyclohexose nucleic acids (WO2011/017521) or tricyclic nucleic acids (WO2013/154798). Modified nucleosides also include nucleosides where the sugar moiety is replaced with a non-sugar moiety, for example in the case of peptide nucleic acids (PNA), or morpholino nucleic acids.

Sugar modifications also include modifications made via altering the substituent groups on the ribose ring to groups other than hydrogen, or the 2′—OH group naturally found in DNA and RNA nucleosides. Substituents may, for example be introduced at the 2′, 3′, 4′ or 5′ positions. Nucleosides with modified sugar moieties also include 2′ modified nucleosides, such as 2′ substituted nucleosides. Indeed, much focus has been spent on developing 2′ substituted nucleosides, and numerous 2′ substituted nucleosides have been found to have beneficial properties when incorporated into oligonucleotides, such as enhanced nucleoside resistance and enhanced affinity.

2′ Modified Nucleosides.

A 2′ sugar modified nucleoside is a nucleoside which has a substituent other than H or —OH at the 2′ position (2′ substituted nucleoside) or comprises a 2′ linked biradicle, and includes 2′ substituted nucleosides and LNA (2′-4′ biradicle bridged) nucleosides. For example, the 2′ modified sugar may provide enhanced binding affinity and/or increased nuclease resistance to the oligonucleotide. Examples of 2′ substituted modified nucleosides are 2′-O-alkyl-RNA, 2′-O-methyl-RNA, 2′-alkoxy-RNA, 2′-O-methoxyethyl-RNA (MOE), 2′-amino-DNA, 2′-Fluoro-RNA, and 2′-fluoro-ANA (F-ANA). For further examples, please see e.g. Freier & Altmann; Nucl. Acid Res., 1997, 25, 4429-4443 and Uhlmann; Curr. Opinion in Drug Development, 2000, 3(2), 293-213; and Deleavey and Damha, Chemistry and Biology 2012, 19, 937. Below are illustrations of some 2′ substituted modified nucleosides.


Locked Nucleic Acid Nucleosides (LNA).

LNA nucleosides are modified nucleosides which comprise a linker group (referred to as a biradicle or a bridge) between C2′ and C4′ of the ribose sugar ring of a nucleotide. These nucleosides are also termed bridged nucleic acid or bicyclic nucleic acid (BNA) in the literature.

In some embodiments, the modified nucleoside or the LNA nucleosides of the oligomer of the invention has a general structure of the formula I or II:


wherein W is selected from —O—, —S—, —N(Ra)—, —C(RaRb)—, such as, in some embodiments —O—;

    • B designates a nucleobase or modified nucleobase moiety;
    • Z designates an internucleoside linkage to an adjacent nucleoside, or a 5′-terminal group;
    • Z* designates an internucleoside linkage to an adjacent nucleoside, or a 3-terminal group;
    • X designates a group selected from the list consisting of —C(RaRb)—, —C(Ra)═C(Rb)—, —C(Ra)═N—, —O—, —Si(Ra)2—, —S—, —SO2—, —N(Ra)—, and >C═Z
      • In some embodiments, X is selected from the group consisting of: —O—, —S—, NH—, NRaRb, —CH2—, CRaRb, —C(═CH2)—, and —C(═CRaRb)—
      • In some embodiments, X is —O—
    • Y designates a group selected from the group consisting of —C(RaRb)—, —C(Ra)═C(Rb)—, —C(Ra)═N—, —O—, —Si(Ra)2—, —S—, —SO2—, —N(Ra)—, and >C═Z
      • In some embodiments, Y is selected from the group consisting of: —CH2—, —C(RaRb)—, —CH2CH2—, —C(RaRb)—C(RaRb)—, —CH2CH2CH2—, —C(RaRb)C(RaRb)C(RaRb)—, —C(Ra)═C(Rb)—, and —C(Ra)═N—
      • In some embodiments, Y is selected from the group consisting of: —CH2—, —CHRa—, —CHCH3—, CRaRb—
    • or —X—Y— together designate a bivalent linker group (also referred to as a radicle) together designate a bivalent linker group consisting of 1, 2, 3 or 4 groups/atoms selected from the group consisting of —C(RaRb)—, —C(Ra)═C(Rb)—, —C(Ra)═N—, —O—, —Si(Ra)2—, —S—, —SO2—, —N(Ra)—, and >C═Z,
      • In some embodiments, —X—Y— designates a biradicle selected from the groups consisting of: —X—CH2—, —X—CRaRb—, —X—CHRa—, —X—C(HCH3)—, —O—Y—, —O—CH2—, —S—CH2—, —NH—CH2—, —O—CHCH3—, —CH2—O—CH2, —O—CH(CH3CH3)—, —O—CH2—CH2—, OCH2—CH2—CH2—, —O—CH2OCH2—, —O—NCH2—, —C(═CH2)—CH2—, —NRa—CH2—, N—O—CH2, —S—CRaRb— and —S—CHRa—.
      • In some embodiments —X—Y— designates —O—CH2— or —O—CH(CH3)—.
    • wherein Z is selected from —O—, —S—, and —N(Ra)—,
    • and Ra and, when present Rb, each is independently selected from hydrogen, optionally substituted C1-6-alkyl, optionally substituted C2-6-alkenyl, optionally substituted C2-6-alkynyl, hydroxy, optionally substituted C1-6-alkoxy, C2-6-alkoxyalkyl, C2-6-alkenyloxy, carboxy, C1-6-alkoxycarbonyl, C1-6-alkylcarbonyl, formyl, aryl, aryloxy-carbonyl, aryloxy, arylcarbonyl, heteroaryl, heteroaryloxy-carbonyl, heteroaryloxy, heteroarylcarbonyl, amino, mono- and di(C1-6-alkyl)amino, carbamoyl, mono- and di(C1-6-alkyl)-amino-carbonyl, amino-C1-6-alkyl-aminocarbonyl, mono- and di(C1-6-alkyl)amino-C1-6-alkyl-aminocarbonyl, C1-6-alkyl-carbonylamino, carbamido, C1-6-alkanoyloxy, sulphono, C1-6-alkylsulphonyloxy, nitro, azido, sulphanyl, C1-6-alkylthio, halogen, where aryl and heteroaryl may be optionally substituted and where two geminal substituents Ra and Rb together may designate optionally substituted methylene (═CH2), wherein for all chiral centers, asymmetric groups may be found in either R or S orientation,
    • wherein R1, R2, R3, R5 and R5* are independently selected from the group consisting of: hydrogen, optionally substituted C1-6-alkyl, optionally substituted C2-6-alkenyl, optionally substituted C2-6-alkynyl, hydroxy, C1-6-alkoxy, C2-6-alkoxyalkyl, C2-6-alkenyloxy, carboxy, C1-6-alkoxycarbonyl, C1-6-alkylcarbonyl, formyl, aryl, aryloxy-carbonyl, aryloxy, arylcarbonyl, heteroaryl, heteroaryloxy-carbonyl, heteroaryloxy, heteroarylcarbonyl, amino, mono- and di(C1-6-alkyl)amino, carbamoyl, mono- and di(C1-6-alkyl)-amino-carbonyl, amino-C1-6-alkyl-aminocarbonyl, mono- and di(C1-6-alkyl)amino-C1-6-alkyl-aminocarbonyl, C1-6-alkyl-carbonylamino, carbamido, C1-6-alkanoyloxy, sulphono, C1-6-alkylsulphonyloxy, nitro, azido, sulphanyl, C1-6-alkylthio, halogen, where aryl and heteroaryl may be optionally substituted, and where two geminal substituents together may designate oxo, thioxo, imino, or optionally substituted methylene.
      • In some embodiments R1, R2, R3, R5 and R5* are independently selected from C1-6 alkyl, such as methyl, and hydrogen.
      • In some embodiments R1, R2, R3, R5 and R5* are all hydrogen.
      • In some embodiments R1, R2, R3, are all hydrogen, and either R5 and R5* is also hydrogen and the other of R5 and R5* is other than hydrogen, such as C1-6 alkyl such as methyl.
      • In some embodiments, Ra is either hydrogen or methyl. In some embodiments, when present, Rb is either hydrogen or methyl.
      • In some embodiments, one or both of Ra and Rb is hydrogen
      • In some embodiments, one of Ra and Rb is hydrogen and the other is other than hydrogen
      • In some embodiments, one of Ra and Rb is methyl and the other is hydrogen
      • In some embodiments, both of Ra and Rb are methyl.
      • In some embodiments, the biradicle —X—Y— is —O—CH2—, W is O, and all of R1, R2, R3, R5 and R5* are all hydrogen. Such LNA nucleosides are disclosed in WO99/014226, WO00/66604, WO98/039352 and WO2004/046160 which are all hereby incorporated by reference, and include what are commonly known as beta-D-oxy LNA and alpha-L-oxy LNA nucleosides.

In some embodiments, the biradicle —X—Y— is —S—CH2—, W is O, and all of R1, R2, R3, R5 and R5* are all hydrogen. Such thio LNA nucleosides are disclosed in WO99/014226 and WO2004/046160 which are hereby incorporated by reference.

In some embodiments, the biradicle —X—Y— is —NH—CH2—, W is O, and all of R1, R2, R3, R5 and R5* are all hydrogen. Such amino LNA nucleosides are disclosed in WO99/014226 and WO2004/046160 which are hereby incorporated by reference.

In some embodiments, the biradicle —X—Y— is —O—CH2—CH2— or —O—CH2—CH2—CH2—, W is O, and all of R1, R2, R3, R5 and R5* are all hydrogen. Such LNA nucleosides are disclosed in WO00/047599 and Morita et al, Bioorganic & Med. Chem. Lett. 12 73-76, which are hereby incorporated by reference, and include what are commonly known as 2′-O-4′C-ethylene bridged nucleic acids (ENA).

In some embodiments, the biradicle —X—Y— is —O—CH2—, W is O, and all of R1, R2, R3, and one of R5 and R5* are hydrogen, and the other of R5 and R5* is other than hydrogen such as C1-6 alkyl, such as methyl. Such 5′ substituted LNA nucleosides are disclosed in WO2007/134181 which is hereby incorporated by reference.

In some embodiments, the biradicle —X—Y— is —O—CRaRb—, wherein one or both of Ra and Rb are other than hydrogen, such as methyl, W is O, and all of R1, R2, R3, and one of R5 and R5* are hydrogen, and the other of R5 and R5* is other than hydrogen such as C1-6 alkyl, such as methyl. Such bis modified LNA nucleosides are disclosed in WO2010/077578 which is hereby incorporated by reference.

In some embodiments, the biradicle —X—Y— designate the bivalent linker group —O—CH(CH2OCH3)—(2′ O-methoxyethyl bicyclic nucleic acid—Seth at al., 2010, J. Org. Chem. Vol 75(5) pp. 1569-81). In some embodiments, the biradicle —X—Y— designate the bivalent linker group —O—CH(CH2CH3)—(2′O-ethyl bicyclic nucleic acid—Seth at al., 2010, J. Org. Chem. Vol 75(5) pp. 1569-81). In some embodiments, the biradicle —X—Y— is —O—CHRa—, W is O, and all of R1, R2, R3, R5 and R5* are all hydrogen. Such 6′ substituted LNA nucleosides are disclosed in WO10036698 and WO07090071 which are both hereby incorporated by reference.

In some embodiments, the biradicle —X—Y— is —O—CH(CH2OCH3)—, W is O, and all of R1, R2, R3, R5 and R5* are all hydrogen. Such LNA nucleosides are also known as cyclic MOEs in the art (cMOE) and are disclosed in WO07090071.

In some embodiments, the biradicle —X—Y— designate the bivalent linker group —O—CH(CH3)—.—in either the R- or S-configuration. In some embodiments, the biradicle —X—Y— together designate the bivalent linker group —O—CH2—O—CH2—(Seth at al., 2010, J. Org. Chem). In some embodiments, the biradicle —X—Y— is —O—CH(CH3)—, W is O, and all of R1, R2, R3, R5 and R5* are all hydrogen. Such 6′ methyl LNA nucleosides are also known as cET nucleosides in the art, and may be either (S)cET or (R)cET stereoisomers, as disclosed in WO07090071 (beta-D) and WO2010/036698 (alpha-L) which are both hereby incorporated by reference).

In some embodiments, the biradicle —X—Y— is —O—CRaRb—, wherein in neither Ra or Rb is hydrogen, W is O, and all of R1, R2, R3, R5 and R5* are all hydrogen. In some embodiments, Ra and Rb are both methyl. Such 6′ di-substituted LNA nucleosides are disclosed in WO 2009006478 which is hereby incorporated by reference.

In some embodiments, the biradicle —X—Y— is —S—CHRa—, W is O, and all of R1, R2, R3, R5 and R5* are all hydrogen. Such 6′ substituted thio LNA nucleosides are disclosed in WO11156202 which is hereby incorporated by reference. In some 6′ substituted thio LNA embodiments Ra is methyl.

In some embodiments, the biradicle —X—Y— is —C(═CH2)—C(RaRb)—, such as —C(═CH2)—CH2—, or —C(═CH2)—CH(CH3)—W is O, and all of R1, R2, R3, R5 and R5* are all hydrogen. Such vinyl carbo LNA nucleosides are disclosed in WO08154401 and WO09067647 which are both hereby incorporated by reference.

In some embodiments the biradicle —X—Y— is —N(—ORa)—, W is O, and all of R1, R2, R3, R5 and R5* are all hydrogen. In some embodiments Ra is C1-6 alkyl such as methyl. Such LNA nucleosides are also known as N substituted LNAs and are disclosed in WO2008/150729 which is hereby incorporated by reference. In some embodiments, the biradicle —X—Y— together designate the bivalent linker group —O—NRa—CH3-(Seth at al., 2010, J. Org. Chem). In some embodiments the biradicle —X—Y— is —N(Ra)—, W is O, and all of R1, R2, R3, R5 and R5* are all hydrogen. In some embodiments Ra is C1-6 alkyl such as methyl.

In some embodiments, one or both of R5 and R5* is hydrogen and, when substituted the other of R5 and R5* is C1-6 alkyl such as methyl. In such an embodiment, R1, R2, R3, may all be hydrogen, and the biradicle —X—Y— may be selected from —O—CH2— or —O—C(HCRa)—, such as —O—C(HCH3)—.

In some embodiments, the biradicle is —CRaRb—O—CRaRb—, such as CH2—O—CH2—, W is O and all of R1, R2, R3, R5 and R5* are all hydrogen. In some embodiments Ra is C1-6 alkyl such as methyl. Such LNA nucleosides are also known as conformationally restricted nucleotides (CRNs) and are disclosed in WO2013036868 which is hereby incorporated by reference.

In some embodiments, the biradicle is —O—CRaRb—O—CRaRb—, such as O—CH2—O—CH2—, W is O and all of R1, R2, R3, R5 and R5* are all hydrogen. In some embodiments Ra is C1-6 alkyl such as methyl. Such LNA nucleosides are also known as COC nucleotides and are disclosed in Mitsuoka et al., Nucleic Acids Research 2009 37(4), 1225-1238, which is hereby incorporated by reference.

It will be recognized than, unless specified, the LNA nucleosides may be in the beta-D or alpha-L stereoisoform.

Certain examples of LNA nucleosides are presented in Scheme 1.

As illustrated in the examples, in preferred embodiments of the invention the LNA nucleosides in the oligonucleotides are beta-D-oxy-LNA nucleosides.

Nuclease Mediated Degradation

Nuclease mediated degradation refers to an oligonucleotide capable of mediating degradation of a complementary nucleotide sequence when forming a duplex with such a sequence.

In some embodiments, the oligonucleotide may function via nuclease mediated degradation of the target nucleic acid, where the oligonucleotides of the invention are capable of recruiting a nuclease, particularly and endonuclease, preferably endoribonuclease (RNase), such as RNase H. Examples of oligonucleotide designs which operate via nuclease mediated mechanisms are oligonucleotides which typically comprise a region of at least 5 or 6 DNA nucleosides and are flanked on one side or both sides by affinity enhancing nucleosides, for example gapmers, headmers and tailmers.

RNase H Activity and Recruitment

The RNase H activity of an antisense oligonucleotide refers to its ability to recruit RNase H when in a duplex with a complementary RNA molecule. WO01/23613 provides in vitro methods for determining RNaseH activity, which may be used to determine the ability to recruit RNaseH. Typically an oligonucleotide is deemed capable of recruiting RNase H if it, when provided with a complementary target nucleic acid sequence, has an initial rate, as measured in pmol/l/min, of at least 10% or more than 20% of the of the initial rate determined when using a oligonucleotide having the same base sequence as the modified oligonucleotide being tested, but containing only DNA monomers, with phosphorothioate linkages between all monomers in the oligonucleotide, and using the methodology provided by Example 91-95 of WO01/23613 (hereby incorporated by reference).

Gapmer

The term gapmer as used herein refers to an antisense oligonucleotide which comprises a region of RNase H recruiting oligonucleotides (gap) which is flanked 5′ and 3′ by one or more affinity enhancing modified nucleosides (flanks). Various gapmer designs are described herein. Headmers and tailmers are oligonucleotides capable of recruiting RNase H where one of the flanks is missing, i.e. only one of the ends of the oligonucleotide comprises affinity enhancing modified nucleosides. For headmers the 3′ flank is missing (i.e. the 5′ flanc comprise affinity enhancing modified nucleosides) and for tailmers the 5′ flank is missing (i.e. the 3′ flank comprises affinity enhancing modified nucleosides).

LNA Gapmer

The term LNA gapmer is a gapmer oligonucleotide wherein at least one of the affinity enhancing modified nucleosides is an LNA nucleoside.

Mixed Wing Gapmer

The term mixed wing gapmer refers to a LNA gapmer wherein the flank regions comprise at least one LNA nucleoside and at least one non-LNA modified nucleoside, such as at least one 2′ substituted modified nucleoside, such as, for example, 2′-O-alkyl-RNA, 2′-O-methyl-RNA, 2′-alkoxy-RNA, 2′-O-methoxyethyl-RNA (MOE), 2′-amino-DNA, 2′-Fluoro-RNA, and 2′-F-ANA nucleoside(s). In some embodiments the mixed wing gapmer has one flank which comprises LNA nucleosides (e.g. 5′ or 3′) and the other flank (3′ or 5′ respectfully) comprises 2′ substituted modified nucleoside(s).

Conjugate

The term conjugate as used herein refers to an oligonucleotide which is covalently linked to a non-nucleotide moiety (conjugate moiety or region C or third region).

Conjugation of the oligonucleotide of the invention to one or more non-nucleotide moieties may improve the pharmacology of the oligonucleotide, e.g. by affecting the activity, cellular distribution, cellular uptake or stability of the oligonucleotide. In some embodiments the conjugate moiety modify or enhance the pharmacokinetic properties of the oligonucleotide by improving cellular distribution, bioavailability, metabolism, excretion, permeability, and/or cellular uptake of the oligonucleotide. In particular the conjugate may target the oligonucleotide to a specific organ, tissue or cell type and thereby enhance the effectiveness of the oligonucleotide in that organ, tissue or cell type. A the same time the conjugate may serve to reduce activity of the oligonucleotide in non-target cell types, tissues or organs, e.g. off target activity or activity in non-target cell types, tissues or organs. WO 93/07883 and WO 2013/033230 provides suitable conjugate moieties, which are hereby incorporated by reference. WO 2012/143379 provides a method of delivering a drug across the blood-brain-barrier by conjugation to an antibody fragment with affinity to the transferrin receptor, which are hereby incorporated by reference.

Oligonucleotide conjugates and their synthesis has also been reported in comprehensive reviews by Manoharan in Antisense Drug Technology, Principles, Strategies, and Applications, S. T. Crooke, ed., Ch. 16, Marcel Dekker, Inc., 2001 and Manoharan, Antisense and Nucleic Acid Drug Development, 2002, 12, 103, each of which is incorporated herein by reference in its entirety.

In an embodiment, the non-nucleotide moiety (conjugate moiety) is selected from the group consisting of carbohydrates, cell surface receptor ligands, drug substances, hormones, lipophilic substances, polymers, proteins, peptides, toxins (e.g. bacterial toxins), vitamins, viral proteins (e.g. capsids) or combinations thereof. In some embodiments the non-nucleotide moiety an antibody or antibody fragment, such as an antibody or antibody fragment that facilitates delivery across the blood-brain-barrier, in particular an antibody or antibody fragment targeting the transferrin receptor.

Linkers

A linkage or linker is a connection between two atoms that links one chemical group or segment of interest to another chemical group or segment of interest via one or more covalent bonds. Conjugate moieties can be attached to the oligonucleotide directly or through a linking moiety (e.g. linker or tether). Linkers serve to covalently connect a third region, e.g. a conjugate moiety (Region C), to a first region, e.g. an oligonucleotide (region A).

In some embodiments of the invention the conjugate or oligonucleotide conjugate of the invention may optionally, comprise a linker region (second region or region B and/or region Y) which is positioned between the oligonucleotide (region A or first region) and the conjugate moiety (region C or third region).

Region B refers to biocleavable linkers comprising or consisting of a physiologically labile bond that is cleavable under conditions normally encountered or analogous to those encountered within a mammalian body. Conditions under which physiologically labile linkers undergo chemical transformation (e.g., cleavage) include chemical conditions such as pH, temperature, oxidative or reductive conditions or agents, and salt concentration found in or analogous to those encountered in mammalian cells. Mammalian intracellular conditions also include the presence of enzymatic activity normally present in a mammalian cell such as from proteolytic enzymes or hydrolytic enzymes or nucleases. In one embodiment the biocleavable linker is susceptible to S1 nuclease cleavage. In a preferred embodiment the nuclease susceptible linker comprises between 1 and 10 nucleosides, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 nucleosides, more preferably between 2 and 6 nucleosides and most preferably between 2 and 4 linked nucleosides comprising at least two consecutive phosphodiester linkages, such as at least 3 or 4 or 5 consecutive phosphodiester linkages. Preferably the nucleosides are DNA or RNA. Phosphodiester containing biocleavable linkers are described in more detail in WO 2014/076195 (hereby incorporated by reference).

Region Y refers to linkers that are not necessarily biocleavable but primarily serve to covalently connect a conjugate moiety (region C or third region), to an oligonucleotide (region A or first region). The region Y linkers may comprise a chain structure or an oligomer of repeating units such as ethylene glycol, amino acid units or amino alkyl groups The oligonucleotide conjugates of the present invention can be constructed of the following regional elements A-C, A-B-C, A-B-Y-C, A-Y-B-C or A-Y-C. In some embodiments the linker (region Y) is an amino alkyl, such as a C2-C36 amino alkyl group, including, for example C6 to C12 amino alkyl groups. In a preferred embodiment the linker (region Y) is a C6 amino alkyl group.

Control

By the term “control” when used in relation to measurements of the effect of an oligonucleotide it is generally understood that the control is an untreated individual or target cell or a individual or target cell treated with a non-targeting oligonucleotide (mock). It may however also be an individual treated with the standard of care.

Treatment

The term ‘treatment’ as used herein refers to both treatment of an existing disease (e.g. a disease or disorder as herein referred to), or prevention of a disease, i.e. prophylaxis. It will therefore be recognized that treatment as referred to herein may, in some embodiments, be prophylactic.

DETAILED DESCRIPTION OF THE INVENTION

The Target

An aspect of the invention is to modulate the level of pig, primate or human UBE3A protein expression, in particular to increase the expression of paternal UBE3A expression in neuronal cells, in particular in human neuronal cells. The human UBE3A protein exists in several isoforms which are listed under Uniprot nr. Q05086. Several mutations in the maternal UBE3A gene can results in Angelman syndrome.

The target nucleic acid for the oligonucleotides of the invention is RNA, in particular a long non-coding RNA. The long non-coding RNA which is targeted by the oligonucleotides of the present invention is human SNHG14 (also known as UBE3A-ATS with Ensembl entry number ENSG00000224078, version GRCh38.p2). In particular the target nucleic acid is the region downstream of SNORD109B corresponding to position 25278410 to 25419462 on chromosome 15 (SEQ ID NO: 1). In Rhesus monkey (Macaca mulatta) the UBE3A supressor is defined as region downstream of SNORD109A corresponding to position 4222848 to U.S. Pat. No. 4,373,084 (forward strand) on chromosome 7 using the Ensembl assembly MMUL 1.0 (SEQ ID NO: 2).

In some embodiments, the target nucleic acid is SEQ ID NO: 1, or naturally occurring variants thereof.

In certain embodiments the target nucleic acid correspond to regions which are conserved between human (SEQ ID NO: 1) and Rhesus monkey (SEQ ID NO: 2). In certain embodiments target nucleic acid correspond to regions which are conserved between human (SEQ ID NO:1), Rhesus monkey (SEQ ID NO: 2) and mouse (SEQ ID NO: 3).

In certain embodiments the target nucleic acid is the region that is antisense to the UBE3A pre-mRNA, this region corresponds to position 55319 to 141053 of SEQ ID NO: 1.

In certain embodiments the target nucleic acid is the region that is downstream of SNORD109B and upstream of the region that is antisense to the UBE3A pre-mRNA, this region corresponds to position 1 to 55319 of SEQ ID NO: 1.

In some embodiments, the target nucleic acid is present in a cell, such as a mammalian cell in particular a human cell in vitro or in vivo (the target cell). In certain embodiments the target cell is a neuron, preferably a human neuronal cell.

The target sequence may be a sub-sequence of the target nucleic acid. In some embodiments the oligonucleotide targets sub-sequence selected from the group consisting of the antisense region of exon 9, exon10, exon13, exon14, intron 14, exon 15, intron15 and exon 16 of UBE3A. In some embodiments the oligonucleotide or contiguous nucleotide sequence hybridize or is complementary to a single stranded nucleic acid molecule selected from the group consisting of positions: 55319-76274, 77483-77573, 92157-93403 and 97056-97354 of SEQ ID NO: 1. In some embodiments the oligonucleotide or contiguous nucleotide sequence hybridize or is complementary to a single stranded nucleic acid molecule selected from the group consisting of positions: 60821-60849, 77567-77583, 92323-92339 and 97156-97172 of SEQ ID NO: 1.

In some embodiments the target nucleic acid is a region corresponding to positions 9200-9250 of SEQ ID NO: 1.

In some embodiments the target nucleic acid is a region corresponding to positions 11505-11555 of SEQ ID NO: 1.

In some embodiments the target nucleic acid is a region corresponding to positions 15100-15150 of SEQ ID NO: 1.

In some embodiments the target nucleic acid is a region corresponding to positions 30590-30740 of SEQ ID NO: 1.

In some embodiments the target nucleic acid is a region corresponding to positions 46380-46430 of SEQ ID NO: 1.

The Oligonucleotides of the Invention

The invention relates to oligonucleotides capable of modulating expression of paternal UBE3A, in particular induction or up-regulation of paternally expressed UBE3A in neuronal cells. The modulation is achieved by hybridizing to a target nucleic acid located on the long non-coding RNA SNHG14 transcript downstream of SNORD109B. In certain embodiments the oligonucleotide of the invention hybridizes to a sub-sequence of the target nucleic acid of SEQ ID NO: 1 with a ΔG° below −10 kcal, such as with a ΔG° between −10 to −60 kcal, such as −12 to −40, such as from −15 to −30 kcal or −16 to −27 kcal such as −18 to −25 kcal.

The oligonucleotide of the invention is an antisense oligonucleotide which targets the pig, rhesus monkey and/or human SNHG14 transcript downstream of SNORD109B.

In some embodiments the antisense oligonucleotide of the invention is capable of modulating the expression of the target by removing, interfering with or decreasing the suppressor of the target. Preferably, the oligonucleotides of the invention induce UBE3A expression in a cell, in particular paternal UBE3A expression in a neuron, by degradation or removal of the SNHG14 transcript downstream of SNORD109B. In some embodiments the oligonucleotides of the invention are capable of increasing the expression of UBE3A by least 20% compared to the expression level of UBE3A in a neuronal cell treated with saline or a non-targeting oligonucleotide, more preferably by at least 30%, 35%, 40%, 45%, 50%, 55%, 60%, 80%, 100%, 120%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240% or 250% compared to the expression level of UBE3A in a neuronal cell treated with saline or a non-targeting oligonucleotide. In additional embodiments the oligonucleotides of the invention are capable of decreasing the level of the SNHG14 transcript downstream of SNORD109B (in particular the part of the transcript that is antisense to the UBE3A pre-mRNA region) by at least 20% compared to the level of the SNHG14 transcript downstream of SNORD109B in a neuronal cell treated with saline or a non-targeting oligonucleotide, more preferably by at least 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95% compared to the level of the SNHG14 transcript downstream of SNORD109B in a neuronal cell treated with saline or a non-targeting oligonucleotide, without reducing SNORD115 levels by more than 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25% or 30% compared to the level of SNORD115 in a cell treated with saline or a non-targeting oligonucleotide. SNRPN and SNORD116 transcripts are located upstream from the SNORD115 transcript consequently if the SNORD115 transcript is not reduced by the oligonucleotide it is highly likely that the SNRPN and SNORD116 transcripts are also not reduced. In a further embodiment SNRPN and SNORD116 transcripts levels are not reduced by more than 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25% or 30% compared to the level of SNRPN and SNORD116 in a cell treated with saline or a non-targeting oligonucleotide.

The target modulation is triggered by the hybridization between a contiguous nucleotide sequence of the oligonucleotide and the target nucleic acid. In some embodiments the oligonucleotide of the invention comprises mismatches between the oligonucleotide and the target nucleic acid. Despite mismatches hybridization to the target nucleic acid may still be sufficient to show a desired modulation of UBE3A expression. Reduced binding affinity resulting from mismatches may advantageously be compensated by increased number of nucleotides in the oligonucleotide and/or an increased number of modified nucleosides capable of increasing the binding affinity to the target, such as 2′ modified nucleosides, including LNA, present within the oligonucleotide sequence.

An aspect of the present invention relates to an antisense oligonucleotide which comprises a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90%, such as 95%, such as 98% such as 100% complementarity to position 25278410 to 25419462 on human chromosome 15.

In some embodiments, the oligonucleotide comprises a contiguous sequence which is at least 90% complementary, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, or 100% complementary with a region of the target nucleic acid shown as SEQ ID NO: 1, 2 or 3.

In a preferred embodiment the oligonucleotide of the invention, or contiguous nucleotide sequence thereof is fully complementary (100% complementary) to a region of the target nucleic acid shown as SEQ ID NO: 1, or in some embodiments may comprise one or two mismatches between the oligonucleotide and the target nucleic acid.

In some embodiments the oligonucleotide sequence is 100% complementary to a corresponding target nucleic acid region present in SEQ ID NO: 1 and SEQ ID NO: 2. In some embodiments the oligonucleotide sequence is 100% complementary to a corresponding target nucleic acid region present SEQ ID NO: 1, 2 and 3.

In some embodiments, the oligonucleotide comprises a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary, such as 100% complementarity, to a corresponding target nucleic acid region present in SEQ ID NO: 1, wherein the target nucleic acid region is selected from the group consisting of region A1 to A3649 in table 1

TABLE 1 Regions of SEQ ID NO 1 which may be targeted using oligonucleotide of the invention Position in Reg. SEQ ID NO 1 A from to Length 1 10 75 66 2 77 91 15 3 93 108 16 4 168 213 46 5 217 282 66 6 284 299 16 7 301 328 28 8 330 344 15 9 361 400 40 10 415 447 33 11 449 470 22 12 472 487 16 13 489 521 33 14 523 540 18 15 551 570 20 16 590 638 49 17 652 670 19 18 672 733 62 19 735 756 22 20 758 773 16 21 781 829 49 22 831 870 40 23 882 903 22 24 918 949 32 25 961 990 30 26 1007 1021 15 27 1019 1050 32 28 1052 1090 39 29 1092 1139 48 30 1147 1179 33 31 1175 1212 38 32 1220 1242 23 33 1245 1259 15 34 1265 1278 14 35 1285 1323 39 36 1317 1330 14 37 1337 1355 19 38 1357 1403 47 39 1405 1421 17 40 1423 1481 59 41 1486 1515 30 42 1521 1581 61 43 1611 1633 23 44 1631 1644 14 45 1635 1663 29 46 1669 1684 16 47 1685 1709 25 48 1711 1724 14 49 1726 1746 21 50 1754 1808 55 51 1819 1860 42 52 1862 1878 17 53 1896 1910 15 54 1923 1944 22 55 1946 1987 42 56 1985 2051 67 57 2053 2082 30 58 2088 2104 17 59 2106 2125 20 60 2132 2207 76 61 2209 2234 26 62 2247 2261 15 63 2263 2286 24 64 2290 2306 17 65 2308 2329 22 66 2347 2391 45 67 2398 2431 34 68 2447 2468 22 69 2470 2555 86 70 2565 2579 15 71 2579 2592 14 72 2589 2605 17 73 2594 2657 64 74 2672 2687 16 75 2692 2705 14 76 2703 2721 19 77 2770 2824 55 78 2826 2841 16 79 2838 2851 14 80 2843 2889 47 81 2896 2930 35 82 2930 2967 38 83 2965 2988 24 84 2984 3028 45 85 3024 3080 57 86 3081 3135 55 87 3140 3176 37 88 3168 3189 22 89 3197 3222 26 90 3212 3226 15 91 3221 3248 28 92 3243 3256 14 93 3250 3264 15 94 3266 3292 27 95 3326 3343 18 96 3345 3391 47 97 3400 3422 23 98 3424 3441 18 99 3434 3447 14 100 3443 3503 61 101 3495 3508 14 102 3505 3558 54 103 3589 3609 21 104 3611 3641 31 105 3662 3696 35 106 3698 3719 22 107 3723 3790 68 108 3810 3854 45 109 3858 3873 16 110 3902 3968 67 111 3971 4009 39 112 4005 4018 14 113 4011 4030 20 114 4032 4077 46 115 4082 4114 33 116 4123 4140 18 117 4150 4164 15 118 4166 4183 18 119 4185 4243 59 120 4248 4268 21 121 4284 4313 30 122 4317 4348 32 123 4364 4471 108 124 4473 4491 19 125 4494 4519 26 126 4521 4535 15 127 4545 4560 16 128 4567 4606 40 129 4616 4714 99 130 4725 4755 31 131 4757 4786 30 132 4788 4852 65 133 4856 4910 55 134 4912 4935 24 135 4937 4970 34 136 4972 5010 39 137 5058 5078 21 138 5080 5116 37 139 5110 5124 15 140 5135 5166 32 141 5168 5201 34 142 5203 5247 45 143 5261 5276 16 144 5278 5293 16 145 5314 5330 17 146 5332 5382 51 147 5398 5414 17 148 5427 5456 30 149 5458 5471 14 150 5487 5500 14 151 5506 5545 40 152 5561 5577 17 153 5580 5617 38 154 5607 5620 14 155 5619 5642 24 156 5644 5683 40 157 5685 5698 14 158 5713 5759 47 159 5756 5769 14 160 5784 5803 20 161 5801 5865 65 162 5873 5905 33 163 5907 5937 31 164 5939 5985 47 165 5987 6017 31 166 6016 6039 24 167 6028 6092 65 168 6102 6127 26 169 6127 6152 26 170 6151 6171 21 171 6178 6206 29 172 6217 6234 18 173 6224 6270 47 174 6272 6289 18 175 6291 6310 20 176 6312 6357 46 177 6367 6389 23 178 6396 6422 27 179 6440 6454 15 180 6456 6482 27 181 6484 6513 30 182 6505 6519 15 183 6518 6553 36 184 6552 6565 14 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3031 117534 117590 57 3032 117582 117604 23 3033 117593 117617 25 3034 117621 117648 28 3035 117640 117662 23 3036 117664 117688 25 3037 117690 117711 22 3038 117728 117743 16 3039 117747 117781 35 3040 117784 117801 18 3041 117792 117822 31 3042 117824 117842 19 3043 117850 117869 20 3044 117890 117940 51 3045 117936 117968 33 3046 117970 117990 21 3047 117989 118034 46 3048 118034 118057 24 3049 118061 118083 23 3050 118086 118122 37 3051 118122 118182 61 3052 118172 118186 15 3053 118197 118211 15 3054 118216 118275 60 3055 118291 118316 26 3056 118318 118354 37 3057 118373 118388 16 3058 118391 118405 15 3059 118407 118423 17 3060 118425 118456 32 3061 118465 118492 28 3062 118498 118521 24 3063 118533 118551 19 3064 118553 118581 29 3065 118587 118617 31 3066 118620 118679 60 3067 118687 118716 30 3068 118731 118771 41 3069 118779 118805 27 3070 118816 118830 15 3071 118832 118895 64 3072 118910 119065 156 3073 119067 119081 15 3074 119095 119140 46 3075 119170 119205 36 3076 119210 119232 23 3077 119230 119246 17 3078 119236 119252 17 3079 119255 119274 20 3080 119271 119284 14 3081 119290 119307 18 3082 119320 119335 16 3083 119357 119463 107 3084 119465 119483 19 3085 119485 119535 51 3086 119550 119571 22 3087 119577 119608 32 3088 119610 119646 37 3089 119648 119688 41 3090 119713 119752 40 3091 119743 119784 42 3092 119786 119800 15 3093 119822 119836 15 3094 119830 119847 18 3095 119849 119900 52 3096 119912 119925 14 3097 119960 119982 23 3098 119984 120013 30 3099 120038 120054 17 3100 120057 120090 34 3101 120092 120134 43 3102 120138 120154 17 3103 120157 120189 33 3104 120187 120200 14 3105 120191 120211 21 3106 120225 120239 15 3107 120242 120267 26 3108 120271 120301 31 3109 120320 120340 21 3110 120363 120406 44 3111 120406 120421 16 3112 120414 120468 55 3113 120457 120470 14 3114 120487 120518 32 3115 120545 120563 19 3116 120567 120587 21 3117 120589 120625 37 3118 120619 120633 15 3119 120650 120663 14 3120 120676 120694 19 3121 120703 120717 15 3122 120721 120737 17 3123 120755 120812 58 3124 120816 120838 23 3125 120843 120871 29 3126 120873 120899 27 3127 120903 120922 20 3128 120933 120946 14 3129 120936 120981 46 3130 120983 121004 22 3131 121006 121021 16 3132 121023 121036 14 3133 121035 121061 27 3134 121063 121079 17 3135 121081 121097 17 3136 121105 121134 30 3137 121138 121156 19 3138 121155 121168 14 3139 121158 121174 17 3140 121166 121189 24 3141 121194 121208 15 3142 121201 121218 18 3143 121213 121237 25 3144 121246 121271 26 3145 121298 121314 17 3146 121311 121324 14 3147 121327 121351 25 3148 121359 121388 30 3149 121390 121419 30 3150 121446 121462 17 3151 121468 121487 20 3152 121499 121515 17 3153 121517 121543 27 3154 121545 121564 20 3155 121575 121597 23 3156 121599 121617 19 3157 121619 121662 44 3158 121664 121681 18 3159 121683 121700 18 3160 121702 121751 50 3161 121773 121788 16 3162 121790 121805 16 3163 121807 121834 28 3164 121836 121857 22 3165 121859 121874 16 3166 121877 121925 49 3167 121923 121936 14 3168 121928 121943 16 3169 121962 121976 15 3170 121978 121992 15 3171 122004 122028 25 3172 122030 122056 27 3173 122046 122059 14 3174 122052 122072 21 3175 122080 122095 16 3176 122099 122122 24 3177 122143 122163 21 3178 122169 122189 21 3179 122258 122274 17 3180 122289 122309 21 3181 122311 122346 36 3182 122357 122395 39 3183 122446 122468 23 3184 122471 122489 19 3185 122491 122512 22 3186 122526 122541 16 3187 122543 122557 15 3188 122579 122592 14 3189 122606 122653 48 3190 122663 122690 28 3191 122728 122742 15 3192 122757 122770 14 3193 122779 122840 62 3194 122842 122857 16 3195 122900 122923 24 3196 122933 122955 23 3197 122968 123042 75 3198 123055 123076 22 3199 123094 123108 15 3200 123114 123134 21 3201 123143 123160 18 3202 123162 123180 19 3203 123184 123198 15 3204 123200 123235 36 3205 123237 123321 85 3206 123314 123329 16 3207 123342 123360 19 3208 123356 123389 34 3209 123391 123410 20 3210 123412 123453 42 3211 123455 123485 31 3212 123488 123503 16 3213 123506 123524 19 3214 123526 123543 18 3215 123545 123578 34 3216 123598 123634 37 3217 123654 123683 30 3218 123685 123706 22 3219 123710 123774 65 3220 123803 123816 14 3221 123818 123831 14 3222 123896 123939 44 3223 123941 123974 34 3224 123976 124021 46 3225 124026 124040 15 3226 124042 124079 38 3227 124091 124109 19 3228 124158 124185 28 3229 124238 124274 37 3230 124319 124332 14 3231 124335 124373 39 3232 124394 124412 19 3233 124419 124445 27 3234 124450 124470 21 3235 124472 124493 22 3236 124499 124520 22 3237 124522 124561 40 3238 124564 124595 32 3239 124607 124649 43 3240 124662 124729 68 3241 124750 124767 18 3242 124769 124793 25 3243 124812 124828 17 3244 124853 124906 54 3245 124923 124948 26 3246 124958 124986 29 3247 125023 125042 20 3248 125032 125046 15 3249 125065 125083 19 3250 125073 125091 19 3251 125093 125107 15 3252 125132 125149 18 3253 125139 125154 16 3254 125151 125200 50 3255 125201 125274 74 3256 125314 125329 16 3257 125331 125370 40 3258 125372 125386 15 3259 125411 125431 21 3260 125433 125462 30 3261 125475 125562 88 3262 125564 125589 26 3263 125605 125639 35 3264 125641 125699 59 3265 125719 125732 14 3266 125737 125769 33 3267 125815 125829 15 3268 125834 125848 15 3269 125850 125884 35 3270 125899 125966 68 3271 125967 125999 33 3272 126026 126080 55 3273 126097 126115 19 3274 126130 126149 20 3275 126151 126179 29 3276 126186 126238 53 3277 126241 126279 39 3278 126275 126295 21 3279 126297 126312 16 3280 126320 126363 44 3281 126376 126395 20 3282 126406 126419 14 3283 126420 126442 23 3284 126467 126501 35 3285 126503 126538 36 3286 126566 126580 15 3287 126584 126597 14 3288 126620 126653 34 3289 126654 126694 41 3290 126697 126715 19 3291 126764 126777 14 3292 126792 126828 37 3293 126842 126862 21 3294 126866 126879 14 3295 126881 126897 17 3296 126906 126925 20 3297 126956 126987 32 3298 126989 127023 35 3299 127026 127135 110 3300 127142 127174 33 3301 127176 127191 16 3302 127193 127217 25 3303 127229 127253 25 3304 127255 127280 26 3305 127294 127394 101 3306 127396 127415 20 3307 127417 127478 62 3308 127491 127504 14 3309 127506 127530 25 3310 127542 127566 25 3311 127582 127628 47 3312 127654 127675 22 3313 127681 127706 26 3314 127706 127739 34 3315 127769 127792 24 3316 127808 127829 22 3317 127839 127888 50 3318 127900 127932 33 3319 127943 127975 33 3320 127988 128046 59 3321 128048 128069 22 3322 128068 128106 39 3323 128105 128118 14 3324 128121 128157 37 3325 128159 128188 30 3326 128190 128268 79 3327 128279 128317 39 3328 128321 128335 15 3329 128342 128368 27 3330 128374 128446 73 3331 128444 128540 97 3332 128546 128586 41 3333 128588 128640 53 3334 128642 128674 33 3335 128675 128879 205 3336 128881 128936 56 3337 128934 129000 67 3338 129002 129060 59 3339 129074 129100 27 3340 129107 129123 17 3341 129125 129163 39 3342 129168 129230 63 3343 129264 129277 14 3344 129284 129318 35 3345 129320 129346 27 3346 129357 129391 35 3347 129393 129420 28 3348 129447 129485 39 3349 129489 129504 16 3350 129514 129540 27 3351 129550 129563 14 3352 129559 129595 37 3353 129606 129627 22 3354 129633 129681 49 3355 129683 129697 15 3356 129699 129716 18 3357 129706 129738 33 3358 129757 129790 34 3359 129792 129820 29 3360 129812 129846 35 3361 129851 129867 17 3362 129869 129883 15 3363 129885 129915 31 3364 129917 129955 39 3365 129957 130046 90 3366 130042 130070 29 3367 130110 130156 47 3368 130158 130309 152 3369 130311 130373 63 3370 130375 130391 17 3371 130407 130429 23 3372 130439 130461 23 3373 130475 130507 33 3374 130512 130550 39 3375 130552 130582 31 3376 130584 130614 31 3377 130616 130764 149 3378 130766 130869 104 3379 130871 131021 151 3380 131033 131051 19 3381 131092 131105 14 3382 131112 131188 77 3383 131194 131237 44 3384 131233 131247 15 3385 131236 131287 52 3386 131292 131307 16 3387 131314 131333 20 3388 131373 131386 14 3389 131396 131417 22 3390 131419 131439 21 3391 131429 131458 30 3392 131481 131499 19 3393 131676 131689 14 3394 131729 131743 15 3395 131745 131764 20 3396 131785 131807 23 3397 131809 131875 67 3398 131877 131953 77 3399 131955 131980 26 3400 132020 132068 49 3401 132086 132108 23 3402 132118 132138 21 3403 132152 132183 32 3404 132185 132205 21 3405 132219 132232 14 3406 132234 132252 19 3407 132261 132291 31 3408 132319 132337 19 3409 132345 132363 19 3410 132365 132378 14 3411 132414 132483 70 3412 132504 132547 44 3413 132549 132582 34 3414 132584 132602 19 3415 132616 132642 27 3416 132643 132681 39 3417 132685 132714 30 3418 132736 132769 34 3419 132771 132793 23 3420 132809 132825 17 3421 132827 132841 15 3422 132861 132884 24 3423 132882 132900 19 3424 132899 132915 17 3425 132917 132951 35 3426 132940 132954 15 3427 132958 132983 26 3428 132985 133031 47 3429 133032 133051 20 3430 133042 133060 19 3431 133051 133071 21 3432 133073 133087 15 3433 133083 133104 22 3434 133097 133110 14 3435 133131 133199 69 3436 133198 133222 25 3437 133233 133249 17 3438 133251 133284 34 3439 133327 133429 103 3440 133431 133596 166 3441 133588 133602 15 3442 133598 133611 14 3443 133613 133628 16 3444 133628 133646 19 3445 133651 133670 20 3446 133666 133707 42 3447 133718 133742 25 3448 133743 133777 35 3449 133779 133794 16 3450 133821 133851 31 3451 133859 133880 22 3452 133890 133921 32 3453 133923 133974 52 3454 133982 133998 17 3455 134000 134036 37 3456 134065 134107 43 3457 134120 134173 54 3458 134165 134179 15 3459 134187 134200 14 3460 134207 134242 36 3461 134244 134258 15 3462 134260 134273 14 3463 134275 134299 25 3464 134314 134346 33 3465 134356 134371 16 3466 134365 134380 16 3467 134374 134420 47 3468 134445 134477 33 3469 134508 134523 16 3470 134531 134548 18 3471 134542 134555 14 3472 134568 134621 54 3473 134647 134667 21 3474 134679 134719 41 3475 134721 134824 104 3476 134826 134849 24 3477 134856 134869 14 3478 134877 134910 34 3479 134912 134966 55 3480 134960 134980 21 3481 134989 135012 24 3482 135014 135066 53 3483 135074 135093 20 3484 135108 135125 18 3485 135151 135260 110 3486 135264 135277 14 3487 135273 135310 38 3488 135321 135337 17 3489 135340 135365 26 3490 135360 135374 15 3491 135364 135386 23 3492 135388 135430 43 3493 135432 135447 16 3494 135498 135521 24 3495 135519 135545 27 3496 135559 135622 64 3497 135624 135647 24 3498 135656 135673 18 3499 135675 135704 30 3500 135721 135742 22 3501 135753 135796 44 3502 135815 135858 44 3503 135860 135880 21 3504 135883 135915 33 3505 135922 135965 44 3506 135979 135993 15 3507 135995 136036 42 3508 136051 136065 15 3509 136108 136165 58 3510 136173 136190 18 3511 136192 136287 96 3512 136289 136303 15 3513 136317 136346 30 3514 136375 136415 41 3515 136429 136470 42 3516 136472 136496 25 3517 136498 136532 35 3518 136542 136565 24 3519 136643 136657 15 3520 136674 136701 28 3521 136704 136719 16 3522 136715 136728 14 3523 136721 136737 17 3524 136737 136750 14 3525 136783 136810 28 3526 136824 136849 26 3527 136859 136896 38 3528 136898 136927 30 3529 136949 136983 35 3530 136985 137000 16 3531 137053 137071 19 3532 137077 137097 21 3533 137108 137164 57 3534 137166 137196 31 3535 137198 137221 24 3536 137223 137267 45 3537 137276 137359 84 3538 137360 137385 26 3539 137393 137440 48 3540 137438 137496 59 3541 137498 137518 21 3542 137523 137536 14 3543 137539 137572 34 3544 137584 137612 29 3545 137614 137628 15 3546 137630 137644 15 3547 137646 137669 24 3548 137702 137727 26 3549 137731 137745 15 3550 137759 137772 14 3551 137784 137819 36 3552 137832 137858 27 3553 137861 137876 16 3554 137878 137900 23 3555 137909 137925 17 3556 137924 137961 38 3557 137968 137981 14 3558 138011 138033 23 3559 138035 138077 43 3560 138079 138097 19 3561 138224 138238 15 3562 138232 138252 21 3563 138242 138256 15 3564 138255 138284 30 3565 138295 138326 32 3566 138328 138357 30 3567 138359 138389 31 3568 138403 138449 47 3569 138451 138492 42 3570 138500 138515 16 3571 138524 138548 25 3572 138555 138568 14 3573 138571 138589 19 3574 138589 138629 41 3575 138644 138680 37 3576 138697 138710 14 3577 138712 138729 18 3578 138744 138761 18 3579 138776 138801 26 3580 138860 138896 37 3581 138898 138923 26 3582 138925 138965 41 3583 138967 139008 42 3584 139010 139031 22 3585 139029 139043 15 3586 139034 139048 15 3587 139041 139056 16 3588 139055 139074 20 3589 139078 139094 17 3590 139084 139098 15 3591 139092 139116 25 3592 139133 139147 15 3593 139154 139173 20 3594 139175 139192 18 3595 139204 139229 26 3596 139231 139255 25 3597 139257 139270 14 3598 139272 139303 32 3599 139315 139335 21 3600 139337 139372 36 3601 139383 139397 15 3602 139399 139419 21 3603 139423 139437 15 3604 139435 139492 58 3605 139501 139518 18 3606 139508 139521 14 3607 139571 139586 16 3608 139588 139622 35 3609 139636 139655 20 3610 139657 139673 17 3611 139685 139699 15 3612 139724 139795 72 3613 139796 139811 16 3614 139818 139834 17 3615 139836 139857 22 3616 139856 139869 14 3617 139859 139882 24 3618 139891 139920 30 3619 139930 139952 23 3620 139965 139980 16 3621 139982 140011 30 3622 140013 140031 19 3623 140047 140072 26 3624 140074 140099 26 3625 140101 140119 19 3626 140121 140135 15 3627 140144 140158 15 3628 140157 140183 27 3629 140185 140210 26 3630 140231 140262 32 3631 140258 140272 15 3632 140264 140288 25 3633 140290 140325 36 3634 140339 140364 26 3635 140369 140402 34 3636 140428 140451 24 3637 140453 140510 58 3638 140512 140541 30 3639 140556 140621 66 3640 140626 140651 26 3641 140653 140724 72 3642 140726 140789 64 3643 140802 140825 24 3644 140837 140861 25 3645 140863 140896 34 3646 140903 140927 25 3647 140958 140993 36 3648 141001 141014 14 3649 141022 141053 32

In some embodiments, the oligonucleotide comprises a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary, such as 100% complementarity, to a corresponding target nucleic acid region present in SEQ ID NO: 1, wherein the target nucleic acid region is selected from the group consisting of region 1B1 to B400 in table 2

TABLE 2 Regions of SEQ ID NO 1 which may be targeted using oligonucleotide of the invention Position in SEQ ID NO 1 Reg. To From Length B1 225 238 14 B2 1163 1178 16 B3 2526 2539 14 B4 2805 2820 16 B5 3027 3040 14 B6 3208 3222 15 B7 3212 3225 14 B8 3228 3241 14 B9 3243 3256 14 B10 3810 3854 45 B11 4664 4680 17 B12 5516 5529 14 B13 5657 5671 15 B14 5661 5676 16 B15 5964 5977 14 B16 6217 6234 18 B17 6224 6237 14 B18 6408 6422 15 B19 7300 7313 14 B20 7399 7412 14 B21 7541 7564 24 B22 7626 7640 15 B23 7662 7694 33 B24 7791 7806 16 B25 7853 7868 16 B26 8206 8219 14 B27 8443 8456 14 B28 8739 8752 14 B29 9197 9212 16 B30 10189 10203 15 B31 10754 10768 15 B32 10758 10771 14 B33 11790 11803 14 B34 11870 11883 14 B35 11993 12007 15 B36 B11996 12011 16 B37 12017 12040 24 B38 12095 12108 14 B39 12345 12358 14 B40 12721 12734 14 B41 13372 13386 15 B42 13489 13505 17 B43 15576 15590 15 B44 15617 15632 16 B45 15840 15853 14 B46 16041 16054 14 B47 16207 16222 16 B48 16308 16321 14 B49 16349 16362 14 B50 16463 16479 17 B51 16528 16542 15 B52 16543 16556 14 B53 20495 20508 14 B54 20617 20630 14 B55 20960 20977 18 B56 21465 21479 15 B57 21491 21508 18 B58 23479 23496 18 B59 23741 23755 15 B60 25236 25249 14 B61 25323 25336 14 B62 25447 25462 16 B63 25588 25601 14 B64 25853 25867 15 B65 25885 25898 14 B66 26280 26293 14 B67 26388 26404 17 B68 26416 26450 35 B69 26687 26702 16 B70 26706 26719 14 B71 26783 26796 14 B72 27039 27052 14 B73 27251 27265 15 B74 28683 28698 16 B75 29302 29315 14 B76 29304 29317 14 B77 29308 29321 14 B78 29532 29545 14 B79 29974 29987 14 B80 30054 30068 15 B81 30267 30281 15 B82 30623 30638 16 B83 30628 30641 14 B84 30814 30827 14 B85 30881 30894 14 B86 32459 32478 20 B87 37299 37315 17 B88 39083 39096 14 B89 39370 39383 14 B90 39659 39672 14 B91 40814 40831 18 B92 40851 40864 14 B93 41782 41795 14 B94 41873 41886 14 B95 42037 42050 14 B96 42048 42063 16 B97 42096 42116 21 B98 42959 42973 15 B99 43165 43178 14 B100 45926 45939 14 B101 48163 48176 14 B102 52732 52745 14 B103 52984 53015 32 B104 54404 54420 17 B105 55294 55320 27 B106 55337 55350 14 B107 55420 55434 15 B108 55487 55501 15 B109 55623 55638 16 B110 56195 56214 20 B111 56584 56597 14 B112 57267 57282 16 B113 58126 58139 14 B114 58170 58183 14 B115 58295 58309 15 B116 58658 58671 14 B117 58906 58921 16 B118 58988 59005 18 B119 59024 59045 22 B120 59191 59207 17 B121 59236 59251 16 B122 59298 59312 15 B123 59358 59378 21 B124 59400 59413 14 B125 59434 59447 14 B126 59589 59602 14 B127 59620 59642 23 B128 59718 59743 26 B129 59826 59841 16 B130 59843 59864 22 B131 59882 59906 25 B132 59930 59958 29 B133 59959 60004 46 B134 60006 60029 24 B135 60033 60071 39 B136 60139 60171 33 B137 60193 60215 23 B138 60212 60225 14 B139 60231 60244 14 B140 60246 60265 20 B141 60267 60282 16 B142 60292 60309 18 B143 60348 60361 14 B144 60358 60429 72 B145 60427 60517 91 B146 60519 60545 27 B147 60557 60575 19 B148 60580 60593 14 B149 60595 60622 28 B150 60675 60690 16 B151 60697 60713 17 B152 60727 60754 28 B153 60756 60799 44 B154 60801 60817 17 B155 60819 60855 37 B156 61423 61436 14 B157 61592 61605 14 B158 61624 61637 14 B159 61673 61713 41 B160 61715 61731 17 B161 61733 61752 20 B162 61769 61794 26 B163 61805 61825 21 B164 62101 62114 14 B165 62302 62315 14 B166 62436 62449 14 B167 62664 62679 16 B168 62993 63006 14 B169 63098 63111 14 B170 63347 63367 21 B171 63371 63396 26 B172 63385 63398 14 B173 63526 63539 14 B174 65032 65045 14 B175 66556 66569 14 B176 67158 67183 26 B177 67181 67194 14 B178 68007 68021 15 B179 68644 68657 14 B180 69294 69317 24 B181 69306 69323 18 B182 69353 69366 14 B183 70497 70511 15 B184 71600 71613 14 B185 71887 71905 19 B186 72259 72272 14 B187 72589 72602 14 B188 72783 72796 14 B189 73528 73541 14 B190 73783 73800 18 B191 74907 74920 14 B192 75965 75981 17 B193 75983 75998 16 B194 76004 76020 17 B195 76110 76166 57 B196 76186 76205 20 B197 76234 76253 20 B198 76261 76280 20 B199 76369 76382 14 B200 77139 77152 14 B201 77409 77422 14 B202 77478 77524 47 B203 77526 77590 65 B204 77628 77641 14 B205 77688 77701 14 B206 78275 78308 34 B207 78310 78332 23 B208 78340 78356 17 B209 78358 78371 14 B210 78373 78395 23 B211 78397 78440 44 B212 78442 78455 14 B213 78475 78489 15 B214 78696 78709 14 B215 78847 78860 14 B216 79493 79516 24 B217 79705 79718 14 B218 81009 81054 46 B219 81353 81367 15 B220 81970 81986 17 B221 81991 82006 16 B222 82042 82106 65 B223 82278 82291 14 B224 82716 82735 20 B225 84314 84328 15 B226 85628 85665 38 B227 86226 86239 14 B228 86237 86253 17 B229 86566 86579 14 B230 86945 86959 15 B231 87337 87358 22 B232 87662 87675 14 B233 89424 89439 16 B234 89972 89985 14 B235 90782 90795 14 B236 90939 90953 15 B237 90942 90955 14 B238 90965 90981 17 B239 91101 91115 15 B240 92083 92096 14 B241 92164 92177 14 B242 92179 92192 14 B243 92194 92210 17 B244 92212 92236 25 B245 92245 92260 16 B246 92262 92302 41 B247 92304 92321 18 B248 92323 92366 44 B249 92375 92389 15 B250 92392 92405 14 B251 92407 92426 20 B252 92442 92459 18 B253 92497 92516 20 B254 92578 92591 14 B255 92599 92612 14 B256 92614 92651 38 B257 92659 92684 26 B258 92686 92699 14 B259 92704 92726 23 B260 92731 92750 20 B261 92752 92774 23 B262 92780 92795 16 B263 92800 92813 14 B264 92839 92858 20 B265 92860 92891 32 B266 92893 92906 14 B267 92908 92921 14 B268 92923 92941 19 B269 92965 92986 22 B270 92988 93002 15 B271 93044 93059 16 B272 93061 93076 16 B273 93105 93122 18 B274 93142 93209 68 B275 93227 93241 15 B276 93288 93305 18 B277 93325 93344 20 B278 93398 93412 15 B279 93572 93586 15 B280 94509 94522 14 B281 95720 95738 19 B282 97050 97065 16 B283 97079 97098 20 B284 97127 97194 68 B285 97208 97230 23 B286 97232 97284 53 B287 97286 97311 26 B288 97313 97362 50 B289 97368 97383 16 B290 97426 97439 14 B291 98077 98090 14 B292 98227 98240 14 B293 98232 98255 24 B294 99151 99164 14 B295 99405 99418 14 B296 99570 99583 14 B297 99733 99748 16 B298 101829 101842 14 B299 101882 101895 14 B300 101955 101968 14 B301 102202 102215 14 B302 103310 103325 16 B303 103653 103666 14 B304 103908 103923 16 B305 103912 103928 17 B306 103917 103933 17 B307 104971 104984 14 B308 105217 105230 14 B309 105233 105250 18 B310 105443 105457 15 B311 105544 105559 16 B312 106047 106071 25 B313 106061 106074 14 B314 106093 106107 15 B315 106114 106130 17 B316 106243 106256 14 B317 106251 106264 14 B318 106840 106855 16 B319 108113 108130 18 B320 108325 108338 14 B321 108856 108869 14 B322 109109 109122 14 B323 109113 109127 15 B324 109116 109132 17 B325 110301 110314 14 B326 110315 110328 14 B327 110317 110330 14 B328 112528 112546 19 B329 112607 112620 14 B330 114775 114788 14 B331 116322 116335 14 B332 116968 116981 14 B333 117788 117801 14 B334 118034 118057 24 B335 118230 118246 17 B336 118235 118248 14 B337 118870 118883 14 B338 119755 119784 30 B339 119786 119800 15 B340 120363 120406 44 B341 120504 120517 14 B342 121161 121174 14 B343 121330 121347 18 B344 121338 121351 14 B345 123417 123430 14 B346 123464 123481 18 B347 125026 125042 17 B348 127046 127071 26 B349 127090 127103 14 B350 127311 127324 14 B351 127354 127367 14 B352 127363 127379 17 B353 127399 127412 14 B354 127863 127876 14 B355 128134 128148 15 B356 128280 128310 31 B357 128343 128368 26 B358 128444 128457 14 B359 128446 128469 24 B360 128498 128511 14 B361 128511 128524 14 B362 129892 129905 14 B363 130261 130283 23 B364 130375 130388 14 B365 130415 130428 14 B366 130634 130650 17 B367 130667 130717 51 B368 130719 130764 46 B369 130783 130796 14 B370 130798 130820 23 B371 130840 130861 22 B372 130975 130994 20 B373 131112 131132 21 B374 131142 131161 20 B375 131233 131246 14 B376 131729 131743 15 B377 132754 132767 14 B378 132924 132937 14 B379 133174 133190 17 B380 133198 133212 15 B381 133207 133222 16 B382 133476 133489 14 B383 133479 133492 14 B384 133491 133531 41 B385 133533 133550 18 B386 133555 133594 40 B387 134160 134173 14 B388 134165 134178 14 B389 134533 134546 14 B390 136724 136737 14 B391 137438 137463 26 B392 137878 137891 14 B393 138082 138097 16 B394 138233 138252 20 B395 138930 138943 14 B396 138947 138960 14 B397 138950 138963 14 B398 139502 139518 17 B399 139508 139521 14 B400 140978 140991 14

In certain embodiments the oligonucleotide or contiguous nucleotide sequence is complementary to a region (or sub-sequence)(or sub-sequence) of the target nucleic acid, wherein the target nucleic acid region is selected from the group consisting of position 1589-10889, 46089-53989 and 60789-62489 of SEQ ID NO: 1.

In one embodiment the oligonucleotide comprises a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90%, such as 100% complementary to a target nucleic acid sequence of position 55319 to 141053 of SEQ ID NO: 1.

In one embodiment the oligonucleotide comprises a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90%, such as 100% complementary to a target nucleic acid sequence of position 1 to 55318 of SEQ ID NO: 1.

In some embodiments, the oligonucleotide comprises a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid selected from the group corresponding to positions: 55319-76274, 77483-77573, 92157-93403 and 97056-97354 of SEQ ID NO: 1.

In some embodiments the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid selected from the group corresponding to positions: 60821-60849, 77567-77583, 92323-92339 and 97156-97172 of SEQ ID NO: 1.

In some embodiments the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid corresponding to positions: 5218-5240 of SEQ ID NO: 1.

In some embodiments the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid corresponding to positions: 5782-5803 of SEQ ID NO: 1.

In some embodiments the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid corresponding to positions: 8113-8139 of SEQ ID NO: 1.

In some embodiments the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid corresponding to positions: 9200-9250 of SEQ ID NO: 1.

In some embodiments the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid corresponding to positions: 11505-11555 of SEQ ID NO: 1.

In some embodiments the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid corresponding to positions: 13223-13242 of SEQ ID NO: 1.

In some embodiments the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid corresponding to positions 15100-15150 of SEQ ID NO: 1.

In some embodiments the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid corresponding to positions 15113-15180 of SEQ ID NO: 1.

In some embodiments the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid corresponding to positions 29635-29705 of SEQ ID NO: 1.

In some embodiments the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid corresponding to positions 30590-30740 of SEQ ID NO: 1.

In some embodiments the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid corresponding to positions 39800-39855 of SEQ ID NO: 1.

In some embodiments the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid to positions 44435-44460 of SEQ ID NO: 1.

In some embodiments the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid to positions 45245-45270 of SEQ ID NO: 1.

In some embodiments the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid to positions 46380-46430 of SEQ ID NO: 1.

In some embodiments the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid to positions 68915-68940 of SEQ ID NO: 1.

In some embodiments, the oligonucleotide comprises or consists of 8 to 35 nucleotides in length, such as from 10 to 30, such as 11 to 22, such as from 12 to 18, such as from 13 to 17 or 14 to 16 contiguous nucleotides in length. In a preferred embodiment, the oligonucleotide comprises or consists of 15 to 20 nucleotides in length.

In some embodiments, the oligonucleotide or contiguous nucleotide sequence thereof comprises or consists of 22 or less nucleotides, such as 20 or less nucleotides, such as 18 or less nucleotides, such as 14, 15, 16 or 17 nucleotides. It is to be understood that any range given herein includes the range endpoints. Accordingly, if an oligonucleotide is said to include from 10 to 30 nucleotides, both 10 and 30 nucleotides are included.

In some embodiments, the contiguous nucleotide sequence comprises or consists of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 contiguous nucleotides in length. In a preferred embodiment, the oligonucleotide comprises or consists of 16, 17, 18 or 19 nucleotides in length.

In some embodiments, the antisense oligonucleotide or contiguous nucleotide sequence comprises or consists of of 10 to 30 nucleotides in length with at least 90% identity, preferably 100% identity to a sequence selected from the group consisting of SEQ ID NO: 4 to 150 (see motif sequences listed in table 3 in the Examples section).

In some embodiments, the antisense oligonucleotide or contiguous nucleotide sequence comprises or consists of of 10 to 30 nucleotides in length with at least 90% identity, preferably 100% identity to a sequence selected from the group consisting of SEQ ID NO: 4 to 818 (see motif sequences listed in table 3 in the Examples section).

In some embodiments, the antisense oligonucleotide or contiguous nucleotide sequence comprises or consists of of 10 to 30 nucleotides in length with at least 90% identity, preferably 100% identity to a sequence selected from the group consisting of SEQ ID NO: 4 to 678 (see motif sequences listed in table 3 in the Examples section).

In some embodiments, the antisense oligonucleotide or contiguous nucleotide sequence comprises or consists of of 10 to 30 nucleotides in length with at least 90% identity, preferably 100% identity to a sequence selected from the group consisting of SEQ ID NO: 166, 167, 167 or 169 (see motif sequences listed in table 3 in the Examples section).

In some embodiments, the antisense oligonucleotide or contiguous nucleotide sequence comprises or consists of of 10 to 30 nucleotides in length with at least 90% identity, preferably 100% identity to a sequence selected from the group consisting of SEQ ID NO: 570, 571, 572, 679, 680, 681, 682 and 683 (see motif sequences listed in table 3 in the Examples section).

In some embodiments, the antisense oligonucleotide or contiguous nucleotide sequence comprises or consists of of 10 to 30 nucleotides in length with at least 90% identity, preferably 100% identity to a sequence selected from the group consisting of SEQ ID NO: 34, 186, 187, 188, 573, 574, 575, 576, 572, 684, 685, 686, 687, 688, 689, 690, 691, 692, 963, 964, 965 and 696 (see motif sequences listed in table 3 in the Examples section).

In some embodiments, the antisense oligonucleotide or contiguous nucleotide sequence comprises or consists of of 10 to 30 nucleotides in length with at least 90% identity, preferably 100% identity to a sequence selected from the group consisting of SEQ ID NO: 35, 199, 200, 201, 202, 203, 204, 205, 206, 207, 209 and 210 or SEQ ID NO: 582, 583 and 584 (see motif sequences listed in table 3 in the Examples section).

In some embodiments, the antisense oligonucleotide or contiguous nucleotide sequence comprises or consists of of 10 to 30 nucleotides in length with at least 90% identity, preferably 100% identity to a sequence selected from the group consisting of SEQ ID NO: 221, 222, 223, 224, 225, 585, 586, 587, 588, 589, 698, 699, 700, 701, 702, 703, 704, 705, 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717 and 718 (see motif sequences listed in table 3 in the Examples section).

In some embodiments, the antisense oligonucleotide or contiguous nucleotide sequence comprises or consists of of 10 to 30 nucleotides in length with at least 90% identity, preferably 100% identity to a sequence selected from the group consisting of SEQ ID NO: 236, 237, 238, 239, 240 and 590.

In some embodiments, the antisense oligonucleotide or contiguous nucleotide sequence comprises or consists of of 10 to 30 nucleotides in length with at least 90% identity, preferably 100% identity to a sequence selected from the group consisting of SEQ ID NO: 241, 591 and 719 (see motif sequences listed in table 3 in the Examples section).

In some embodiments, the antisense oligonucleotide or contiguous nucleotide sequence comprises or consists of of 10 to 30 nucleotides in length with at least 90% identity, preferably 100% identity to a sequence selected from the group consisting of SEQ ID NO: 46, 47, 48, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 613, 614, 615, 616, 617, 618, 619, 620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 721, 722, 723, 724, 725, 726, 727, 728, 729, 730, 731, 732, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770, 771, 772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 791, 792, 793, 794, 795, 796, 797, 798, 799, 800, 800, 800, 800, 800, 801, 801, 802, 803, 804, 805, 806 and 807 (see motif sequences listed in table 3 in the Examples section).

In some embodiments, the antisense oligonucleotide or contiguous nucleotide sequence comprises or consists of of 10 to 30 nucleotides in length with at least 90% identity, preferably 100% identity to a sequence selected from the group consisting of SEQ ID NO: 331, 332, 638, 639, 640, 808, 809, 810, 811, 812, 813, 814 and 815 (see motif sequences listed in table 3 in the Examples section).

In some embodiments, the antisense oligonucleotide or contiguous nucleotide sequence comprises or consists of of 10 to 30 nucleotides in length with at least 90% identity, preferably 100% identity to a sequence selected from the group consisting of SEQ ID NO: 409, 410, 411, 642, 643, 644, 645, 646, 816, 818 and 818 (see motif sequences listed in table 3 in the Examples section).

It is understood that the contiguous nucleobase sequences (motif sequence) can be modified to for example increase nuclease resistance and/or binding affinity to the target nucleic acid. Modifications are described in the definitions and in the “Oligonucleotide design” section. Table 3 lists preferred designs of each motif sequence.

Oligonucleotide Design

Oligonucleotide design refers to the pattern of nucleoside sugar modifications in the oligonucleotide sequence. The oligonucleotides of the invention comprise sugar-modified nucleosides and may also comprise DNA or RNA nucleosides. In some embodiments, the oligonucleotide comprises sugar-modified nucleosides and DNA nucleosides. Incorporation of modified nucleosides into the oligonucleotide of the invention may enhance the affinity of the oligonucleotide for the target nucleic acid. In that case, the modified nucleosides can be referred to as affinity enhancing modified nucleotides.

In an embodiment, the oligonucleotide comprises at least 1 modified nucleoside, such as at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15 or at least 16 modified nucleosides. In an embodiment the oligonucleotide comprises from 1 to 10 modified nucleosides, such as from 2 to 9 modified nucleosides, such as from 3 to 8 modified nucleosides, such as from 4 to 7 modified nucleosides, such as 6 or 7 modified nucleosides. In some embodiments, at least 1 of the modified nucleosides is a locked nucleic acid (LNA), such as at least 2, such as at least 3, at least 4, at least 5, at least 6, at least 7, or at least 8 of the modified nucleosides are LNA. In a still further embodiment all the modified nucleosides are LNA.

In an embodiment, the oligonucleotide of the invention may comprise modifications, which are independently selected from these three types of modifications (modified sugar, modified nucleobase and modified internucleoside linkage) or a combination thereof. Preferably the oligonucleotide comprises one or more sugar modified nucleosides, such as 2′ sugar modified nucleosides. Preferably the oligonucleotide of the invention comprise the one or more 2′ sugar modified nucleoside independently selected from the group consisting of 2′-O-alkyl-RNA, 2′-O-methyl-RNA, 2′-alkoxy-RNA, 2′-O-methoxyethyl-RNA, 2′-amino-DNA, 2′-fluoro-DNA, arabino nucleic acid (ANA), 2′-fluoro-ANA and LNA nucleosides. Even more preferably the the one or more modified nucleoside is LNA.

In a further embodiment the oligonucleotide comprises at least one modified internucleoside linkage. In a preferred embodiment the the internucleoside linkages within the contiguous nucleotide sequence are phosphorothioate or boranophosphate internucleoside linkages.

In some embodiments, the oligonucleotide of the invention comprise at least one modified nucleoside which is a 2′-MOE-RNA, such as 2, 3, 4, 5, 6, 7, 8, 9 or 10 2′-MOE-RNA nucleoside units. In some embodiments, at least one of said modified nucleoside is 2′-fluoro DNA, such as 2, 3, 4, 5, 6, 7, 8, 9 or 10 2′-fluoro-DNA nucleoside units.

In some embodiments, the oligonucleotide of the invention comprises at least one LNA unit, such as 1, 2, 3, 4, 5, 6, 7, or 8 LNA units, such as from 2 to 6 LNA units, such as from 3 to 7 LNA units, 4 to 8 LNA units or 3, 4, 5, 6 or 7 LNA units. In some embodiments, all the modified nucleosides are LNA nucleosides. In a further embodiment, the oligonucleotide may comprise both beta-D-oxy-LNA, and one or more of the following LNA units: thio-LNA, amino-LNA, oxy-LNA, and/or ENA in either the beta-D or alpha-L configurations or combinations thereof. In a further embodiment, all LNA cytosine units are 5-methyl-cytosine. In a preferred embodiment the oligonucleotide or contiguous nucleotide sequence has at least 1 LNA unit at the 5′ end and at least 2 LNA units at the 3′ end of the nucleotide sequence.

In some embodiments, the oligonucleotide of the invention comprises at least one LNA unit and at least one 2′ substituted modified nucleoside.

In some embodiments of the invention, the oligonucleotide comprise both 2′ sugar modified nucleosides and DNA units. Preferably the oligonucleotide comprise both LNA and DNA units. Preferably, the combined total of LNA and DNA units is 8-30, such as 10-25, preferably 12-22, such as 12-18, even more preferably 11-16. In some embodiments of the invention, the nucleotide sequence of the oligonucleotide, such as the contiguous nucleotide sequence consists of at least one or two LNA units and the remaining nucleotide units are DNA units. In some embodiments the oligonucleotide comprises only LNA nucleosides and naturally occurring nucleosides (such as RNA or DNA, most preferably DNA nucleosides), optionally with modified internucleoside linkages such as phosphorothioate.

In an embodiment of the invention the oligonucleotide of the invention is capable of recruiting RNase H.

Gapmer Design

In a preferred embodiment the oligonucleotide of the invention has a gapmer design or structure also referred herein merely as “Gapmer”. In a gapmer structure the oligonucleotide comprises at least three distinct structural regions a 5′-flank, a gap and a 3′-flank, F-G-F′ in ′5->3′ orientation. In this design, flanking regions F and F′ (also termed wing regions) comprise a contiguous stretch of modified nucleosides, which are complementary to the UBE3A target nucleic acid, while the gap region, G, comprises a contiguous stretch of nucleotides which are capable of recruiting a nuclease, preferably an endonuclease such as RNase, for example RNase H, when the oligonucleotide is in duplex with the target nucleic acid. Nucleosides which are capable of recruiting a nuclease, in particular RNase H, can be selected from the group consisting of DNA, alpha-L-oxy-LNA, 2′-Flouro-ANA and UNA. Regions F and F′, flanking the 5′ and 3′ ends of region G, preferably comprise non-nuclease recruiting nucleosides (nucleosides with a 3′ endo structure), more preferably one or more affinity enhancing modified nucleosides. In some embodiments, the 3′ flank comprises at least one LNA nucleoside, preferably at least 2 LNA nucleosides. In some embodiments, the 5′ flank comprises at least one LNA nucleoside. In some embodiments both the 5′ and 3′ flanking regions comprise a LNA nucleoside. In some embodiments all the nucleosides in the flanking regions are LNA nucleosides. In other embodiments, the flanking regions may comprise both LNA nucleosides and other nucleosides (mixed flanks), such as DNA nucleosides and/or non-LNA modified nucleosides, such as 2′ substituted nucleosides. In this case the gap is defined as a contiguous sequence of at least 5 RNase H recruiting nucleosides (nucleosides with a 2′ endo structure, preferably DNA) flanked at the 5′ and 3′ end by an affinity enhancing modified nucleoside, preferably LNA, such as beta-D-oxy-LNA. Consequently, the nucleosides of the 5′ flanking region and the 3′ flanking region which are adjacent to the gap region are modified nucleosides, preferably non-nuclease recruiting nucleosides. In oligonucleotides with mixed flanks where the flanks comprise DNA the 5′ and 3′ nucleosides are modified nucleosides.

Region F

Region F (5′ flank or 5′ wing) attached to the ′5 end of region G comprises, contains or consists of at least one modified nucleoside such as at least 2, at least 3, at least 4, at least 5, at least 6, at least 7 modified nucleosides. In an embodiment region F comprises or consists of from 1 to 7 modified nucleosides, such as from 2 to 6 modified nucleosides, such as from 2 to 5 modified nucleosides, such as from 2 to 4 modified nucleosides, such as from 1 to 3 modified nucleosides, such as 1, 2, 3 or 4 modified nucleosides. In a further embodiment further additional nucleosides may be attached to the ′5 end of region F, representing a region D preferably comprising 1, 2 or 3 nucleoside units, such as DNA nucleosides. Region D can take the function of a biocleavable (B) linker described in the definition of “Linkers”.

In some embodiments, the modified nucleosides in region F have a 3′ endo structure.

In an embodiment, one or more of the modified nucleosides in region F are 2′ modified nucleosides.

In a further embodiment one or more of the 2′ modified nucleosides in region F are selected from 2′-O-alkyl-RNA units, 2′-O-methyl-RNA, 2′-amino-DNA units, 2′-fluoro-DNA units, 2′-alkoxy-RNA, MOE units, LNA units, arabino nucleic acid (ANA) units and 2′-fluoro-ANA units.

In one embodiment of the invention all the modified nucleosides in region F are LNA nucleosides. In a further embodiment the LNA nucleosides in region F are independently selected from the group consisting of oxy-LNA, thio-LNA, amino-LNA, cET, and/or ENA, in either the beta-D or alpha-L configurations or combinations thereof. In a preferred embodiment region F has at least 1 beta-D-oxy LNA unit, at the 5′ end of the contiguous sequence.

Region G

Region G (gap region) preferably comprise, contain or consist of at least 4, such as at least 5, such as at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15 or at least 16 consecutive nucleosides capable of recruiting the aforementioned nuclease, in particular RNaseH. In a further embodiment region G comprise, contain or consist of from 5 to 12, or from 6 to 10 or from 7 to 9, such as 8 consecutive nucleotide units capable of recruiting aforementioned nuclease.

The nucleoside units in region G, which are capable of recruiting nuclease are in an embodiment selected from the group consisting of DNA, alpha-L-LNA, C4′ alkylated DNA (as described in PCT/EP2009/050349 and Vester et al., Bioorg. Med. Chem. Lett. 18 (2008) 2296-2300, both incorporated herein by reference), arabinose derived nucleosides like ANA and 2′F-ANA (Mangos et al. 2003 J. AM. CHEM. SOC. 125, 654-661), UNA (unlocked nucleic acid) (as described in Fluiter et al., Mol. Biosyst., 2009, 10, 1039 incorporated herein by reference). UNA is unlocked nucleic acid, typically where the bond between C2 and C3 of the ribose has been removed, forming an unlocked “sugar” residue.

In a still further embodiment at least one nucleoside unit in region G is a DNA nucleoside unit, such as from 1 to 16 DNA units, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 DNA units, preferably from 2 to 13 DNA units, such as from 4 to 12 DNA units, more preferably from 5 to 11, or from 10 to 16, 11 to 15 or 12 to 14 DNA units. In some embodiments, region G consists of 100% DNA units. In a preferred embodiment G consists of, most preferably 10, 11, 12, 13, 14 or 15 DNA units.

In further embodiments the region G may consist of a mixture of DNA and other nucleosides capable of mediating RNase H cleavage. Region G may consist of at least 50% DNA, more preferably 60%, 70% or 80% DNA, and even more preferred 90% or 95% DNA.

In a still further embodiment at least one nucleoside unit in region G is an alpha-L-LNA nucleoside unit, such as at least one alpha-L-LNA unit, such as 2, 3, 4, 5, 6, 7, 8 or 9 alpha-L-LNA units. In a further embodiment, region G comprises the least one alpha-L-LNA is alpha-L-oxy-LNA unit. In a further embodiment region G comprises a combination of DNA and alpha-L-LNA nucleoside units.

In some embodiments the size of the contiguous sequence in region G may be longer, such as 15, 16, 17, 18, 19 or 20 nucleoside units.

In some embodiments, nucleosides in region G have a 2′ endo structure.

Region F′

Region F′ (3′ flank or 3′ wing) attached to the ′3 end of region G comprises, contains or consists of at least one modified nucleoside such as at least 2, at least 3, at least 4, at least 5, at least 6, at least 7 modified nucleosides. In an embodiment region F′ comprise or consist of from 1 to 7 modified nucleosides, such as from 2 to 6 modified nucleoside, such as from 2 to 4 modified nucleosides, such as from 1 to 3 modified nucleosides, such as 1, 2, 3 or 4 modified nucleosides. In a further embodiment further additional nucleosides attached to the ′3 end of region F′, representing a region D′, preferably comprising 1, 2 or 3 nucleoside units, such as DNA nucleosides. Region D′ can take the function of a biocleavable (B) linker described, in the section “Linkers”.

In some embodiments, the modified nucleosides in region F′ have a 3′ endo structure.

In a preferred embodiment, modified nucleosides in region F′ is LNA.

In a further embodiment modified nucleosides in region F′ are selected from 2′-O-alkyl-RNA units, 2′-O-methyl-RNA, 2′-amino-DNA units, 2′-fluoro-DNA units, 2′-alkoxy-RNA, MOE units, LNA units, arabino nucleic acid (ANA) units and 2′-fluoro-ANA units.

In one embodiment of the invention all the modified nucleosides in region F′ are LNA nucleosides. In a further embodiment the LNA nucleosides in region F′ are independently selected from the group consisting of oxy-LNA, thio-LNA, amino-LNA, cET and/or ENA, in either the beta-D or alpha-L configurations or combinations thereof. In a preferred embodiment region F′ has at least 2 beta-D-oxy LNA unit, at the 3′ end of the contiguous sequence.

Region D and D′

Region D and D′ can be attached to the 5′ end of region F or the 3′ end of region F′, respectively.

Region D or D′ may independently comprise 1, 2, 3, 4 or 5 additional nucleotides, which may be complementary or non-complementary to the target nucleic acid. In this respect the oligonucleotide of the invention, may in some embodiments comprise a contiguous nucleotide sequence capable of modulating the target which is flanked at the 5′ and/or 3′ end by additional nucleotides. Such additional nucleotides may serve as a nuclease susceptible biocleavable linker (see definition of linkers). In some embodiments the additional 5′ and/or 3′ end nucleotides are linked with phosphodiester linkages, and may be DNA or RNA. In another embodiment, the additional 5′ and/or 3′ end nucleotides are modified nucleotides which may for example be included to enhance nuclease stability or for ease of synthesis. In an embodiment of the oligonucleotide of the invention, comprises a region D and/or D′ in addition to the contiguous nucleotide sequence.

The gapmer oligonucleotide of the present invention can be represented by the following formulae:
F-G-F′; in particular F1-7-G4-12-F′1-7
D-F-G-F′, in particular D1-3-F1-7-G4-12-F′1-7
F-G-F′-D′, in particular F1-7-G4-12-F′1-7-D′1-3
D-F-G-F′-D′, in particular D1-3-F1-7-G4-12-F′1-7-D′1-3

The preferred number and types of nucleosides in regions F, G and F′, D and D′ have been described above. The design of the individual oligonucleotide may also have profound impact on the properties of the oligonucleotide in its use for modulating expression of UBE3A.

In some embodiments the oligonucleotide is a gapmer consisting of 14, 15, 16, 17, 18, 19 or 20 nucleotides in length, wherein each of regions F and F′ independently consists of 2, 3 or 4 modified nucleoside units complementary to a part of the human SNHG14 long non-coding RNA which is antisense to the UBE3A pre-mRNA (the target nucleic acid) and region G consists of 10, 11, 12, 13, 14 or 15 nucleoside units, capable of recruiting nuclease when in duplex with the target nucleic acid.

In a further embodiments, the oligonucleotide is a gapmer wherein each of regions F and F′ independently consists of 2, 3, 4 or 5 modified nucleoside units, such as nucleoside units containing a 2′-O-methoxyethyl-ribose sugar (2′-MOE) or nucleoside units containing a 2′-fluoro-deoxyribose sugar and/or LNA units, and region G consists of 9, 10, 11, 12, 13, 14 or 15 nucleoside units, such as DNA units or other nuclease recruiting nucleosides such as alpha-L-LNA or a mixture of DNA and nuclease recruiting nucleosides.

In a further specific embodiment, the oligonucleotide is a gapmer wherein each of regions F and F′ region consists of two LNA units each, and region G consists of 10, 11, 12, 13, 14 or 15 nucleoside units, preferably DNA units. Specific gapmer designs of this nature include 2-10-2, 2-11-2, 2-12-2, 2-13-2, 2-14-2 and 2-15-2.

In a further specific embodiment, the oligonucleotide is a gapmer wherein each of regions F and F′ independently consists of three LNA units, and region G consists of 10, 11, 12, 13, 14 or 15 nucleoside units, preferably DNA units. Specific gapmer designs of this nature include 3-10-3, 3-11-3, 3-12-3, 3-13-3, 3-14-3 and 3-15-3.

In a further specific embodiment, the oligonucleotide is a gapmer wherein each of regions F and F′ consists of four LNA units each, and region G consists of 10, 11, 12, 13, 14 or 15 nucleoside units, preferably DNA units. Specific gapmer designs of this nature include 4-10-4, 4-11-4, 4-12-4, 4-13-4, 4-14-4 and 4-15-4.

Specific gapmer designs of this nature include F-G-F′ designs selected from a group consisting of a gap with 10 nucleosides and independently 1 to 4 modified nucleosides in the wings including 1-10-1, 2-10-1, 1-10-2, 1-10-3, 3-10-1, 1-10-4, 4-10-1, 2-10-2, 2-10-3, 3-10-2, 2-10-4, 4-10-2, 3-10-3, 3-10-4, 4-10-3 and 4-10-4 gapmers.

Specific gapmer designs of this nature include F-G-F′ designs selected from a group consisting of a gap with 11 nucleosides and independently 1 to 4 modified nucleosides in the wings including, 1-11-1, 2-11-1, 1-11-2, 1-11-3, 3-11-1, 1-11-4, 4-11-1, 2-11-2, 2-11-3, 3-11-2, 2-11-4, 4-11-2, 3-11-3, 3-11-4, 4-11-3 and 4-11-4 gapmers.

Specific gapmer designs of this nature include F-G-F′ designs selected from a group consisting of a gap with 12 nucleosides including, 1-12-1, 2-12-1, 1-12-2, 1-12-3, 3-12-1, 1-12-4, 4-12-1, 2-12-2, 2-12-3, 3-12-2, 2-12-4, 4-12-2, 3-12-3, 3-12-4, 4-12-3 and 4-12-4 gapmers. Specific gapmer designs of this nature include F-G-F′ designs selected from a group consisting of a gap with 13 nucleosides and independently 1 to 4 modified nucleosides in the wings including 1-13-1, 1-13-2, 1-13-3, 3-13-1, 1-13-4, 4-13-1, 2-13-1, 2-13-2, 2-13-3, 3-13-2, 2-13-4, 4-13-2, 3-13-3, 3-13-4, 4-13-3, and 4-13-4 gapmers.

Specific gapmer designs of this nature include F-G-F′ designs selected from a group consisting of a gap with 14 nucleosides and independently 1 to 4 modified nucleosides in the wings including 1-14-1, 1-14-2, 2-14-1, 1-14-3, 3-14-1, 1-14-4, 4-14-1, 2-14-2, 2-14-3, 3-14-2 2-14-4, 4-14-2, 3-14-3, 3-14-4 and 4-14-3 gapmers.

Specific gapmer designs of this nature include F-G-F′ designs selected from a group consisting of a gap with 15 nucleosides and independently 1 to 4 modified nucleosides in the wings including 1-15-1, 1-15-2, 2-15-1, 1-15-3, 3-15-1, 1-15-4, 4-15-1, 2-15-2, 2-15-3, 3-15-2 2-15-4, 4-15-2, 3-15-3, 3-15-4 and 4-15-3 gapmers.

Specific gapmer designs of this nature include F-G-F′ designs selected from a group consisting of a gap with 16 nucleosides and independently 1 to 4 modified nucleosides in the wings including 1-16-1, 1-16-2, 2-16-1, 1-15-3, 3-16-1, 1-16-4, 4-16-1, 2-16-2, 2-16-3, 3-16-2 2-16-4, 4-16-2, 3-16-3, 3-16-4 and 4-16-3 gapmers.

In some embodiments the F-G-F′ design is selected from 2-10-4, 3-10-3 and 4-10-2.

In some embodiments the F-G-F′ design is selected from 2-11-4, 3-11-2, 3-11-3 and 4-11-2.

In some embodiments the F-G-F′ design is selected from 2-12-2, 2-12-3, 2-12-4, 3-12-2, 3-12-3, and 4-12-2.

In some embodiments the F-G-F′ design is selected from 2-13-2, 2-13-3, 2-13-4, 3-13-3 and 4-13-2.

In some embodiments the F-G-F′ design is selected from 2-14-2, 2-14-4, 3-14-3 and 4-14-2.

In some embodiments the F-G-F′ design is selected from 2-15-2 and 2-16-2.

In some embodiments the F-G-F′ design is selected from the designs indicated in table 3.

In all instances the F-G-F′ design may further include region D and/or D′, which may have 1, 2 or 3 nucleoside units, such as DNA units. Preferably, the nucleosides in region F and F′ are modified nucleosides, while nucleotides in region G are preferably unmodified nucleosides.

In each design, the preferred modified nucleoside is LNA.

In another embodiment all the internucleoside linkages in the gap in a gapmer are phosphorothioate and/or boranophosphate linkages. In another embodiment all the internucleoside linkages in the flanks (F and F′ region) in a gapmer are phosphorothioate and/or boranophosphate linkages. In another preferred embodiment all the internucleoside linkages in the D and D′ region in a gapmer are phosphodiester linkages.

For specific gapmers as disclosed herein, when the cytosine (C) residues are annotated as 5-methyl-cytosine, in various embodiments, one or more of the C's present in the oligonucleotide may be unmodified C residues.

Further gapmer designs are disclosed in WO2004/046160, WO2007/146511 and incorporated by reference.

For certain embodiments of the invention, the oligonucleotide is selected from the group of oligonucleotide compounds in table 3.

For certain embodiments of the invention, the oligonucleotide is selected from the group of oligonucleotide compounds with CMP-ID-NO: 4_1 to 150_2.

For certain embodiments of the invention, the oligonucleotide is selected from the group of oligonucleotide compounds with CMP-ID-NO: 4_1 to 678_1.

For certain embodiments of the invention, the oligonucleotide is selected from the group of oligonucleotide compounds with CMP-ID-NO: 4_1 to 818_1 (see oligonucleotide sequences listed in table 3 in the Examples section).

For certain embodiments of the invention, the oligonucleotide is an oligonucleotide compound with CMP-ID-NO: 155_1 or 165_1.

For certain embodiments of the invention, the oligonucleotide is selected from the group of oligonucleotide compounds with CMP-ID-NO: 169_52, 169_50 or 169_56.

For certain embodiments of the invention, the oligonucleotide is selected from the group of oligonucleotide compounds with CMP-ID-NO: 172_1, 272_1, 5727, 572_6 or 572_5.

For certain embodiments of the invention, the oligonucleotide is an oligonucleotide compound with CMP-ID-NO: 175_1.

For certain embodiments of the invention, the oligonucleotide is an oligonucleotide compound with CMP-ID-NO: 178_1.

For certain embodiments of the invention, the oligonucleotide is selected from the group of oligonucleotide compounds with CMP-ID-NO: 573_8, 186_1 or 187_1.

For certain embodiments of the invention, the oligonucleotide is an oligonucleotide compound with CMP-ID-NO: 186_1.

For certain embodiments of the invention, the oligonucleotide is selected from the group of oligonucleotide compounds with CMP-ID-NO: 200_1, 204_1, 206_1, 35_2 or 209_1.

For certain embodiments of the invention, the oligonucleotide is selected from the group of oligonucleotide compounds with CMP-ID-NO: 585_1, 585_8, 586_9, 586_5, 586_8, 586_4 or 586_6.

For certain embodiments of the invention, the oligonucleotide is an oligonucleotide compound with CMP-ID-NO: 233_1.

For certain embodiments of the invention, the oligonucleotide is an oligonucleotide compound with CMP-ID-NO: 237_8 or 590_13.

For certain embodiments of the invention, the oligonucleotide is an oligonucleotide compound with CMP-ID-NO: 220_1.

For certain embodiments of the invention, the oligonucleotide is selected from the group of oligonucleotide compounds with CMP-ID-NO: 591_1, 592_2, 592_4 or 241_9.

For certain embodiments of the invention, the oligonucleotide is selected from the group of oligonucleotide compounds with CMP-ID-NO: 597_4, 598_4, 39_1 or 602_1.

For certain embodiments of the invention, the oligonucleotide is an oligonucleotide compound with CMP-ID-NO: 39_1.

For certain embodiments of the invention, the oligonucleotide is an oligonucleotide compound with CMP-ID-NO: 611_7.

For certain embodiments of the invention, the oligonucleotide is an oligonucleotide compound with CMP-ID-NO: 271_1 or 278_1.

For certain embodiments of the invention, the oligonucleotide is selected from the group of oligonucleotide compounds with CMP-ID-NO: 616_4, 621_2, 621_1, 622_3, 622_5, 622_4, 624_3, 624_5, 287_1, 625_6, 626_7, 626_8, 626_9, 48_1, 631_6, 631_1, 303_1, 304_6 or 304_10.

For certain embodiments of the invention, the oligonucleotide is an oligonucleotide compound with CMP-ID-NO: 636_8.

For certain embodiments of the invention, the oligonucleotide is selected from the group of oligonucleotide compounds with CMP-ID-NO: 638_8, 639_5, 331_1 or 640_4.

For certain embodiments of the invention, the oligonucleotide is selected from the group of oligonucleotide compounds with CMP-ID-NO: 359_1, 361_1, 361_5, 362_1 or 641_5.

For certain embodiments of the invention, the oligonucleotide is selected from the group of oligonucleotide compounds with CMP-ID-NO: 378_1, 379_1, 399_1.

For certain embodiments of the invention, the oligonucleotide is selected from the group of oligonucleotide compounds with CMP-ID-NO: 403_1, 405_1, 642_12, 642_13, 644_3 or 646_16.

For certain embodiments of the invention, the oligonucleotide is an oligonucleotide compound with CMP-ID-NO: 85_1 or 425_5.

For certain embodiments of the invention, the oligonucleotide is an oligonucleotide compound with CMP-ID-NO:116_1.

For certain embodiments of the invention, the oligonucleotide is an oligonucleotide compound with CMP-ID-NO: 123_1 or 124_1.

For certain embodiments of the invention, the oligonucleotide is an oligonucleotide compound with CMP-ID-NO: 126_2.

Method of Manufacture

In a further aspect, the invention provides methods for manufacturing the oligonucleotides of the invention comprising reacting nucleotide units and thereby forming covalently linked contiguous nucleotide units comprised in the oligonucleotide. Preferably, the method uses phophoramidite chemistry (see for example Caruthers et al, 1987, Methods in Enzymology vol. 154, pages 287-313). In a further embodiment the method further comprises reacting the contiguous nucleotide sequence with a conjugating moiety (ligand). In a further aspect a method is provided for manufacturing the composition of the invention, comprising mixing the oligonucleotide or conjugated oligonucleotide of the invention with a pharmaceutically acceptable diluent, solvent, carrier, salt and/or adjuvant.

Pharmaceutical Composition

In a further aspect, the invention provides pharmaceutical compositions comprising any of the aforementioned oligonucleotides and/or oligonucleotide conjugates and a pharmaceutically acceptable diluent, carrier, salt and/or adjuvant. A pharmaceutically acceptable diluent includes phosphate-buffered saline (PBS) and pharmaceutically acceptable salts include, but are not limited to, sodium and potassium salts.

WO 2007/031091 provides suitable and preferred examples of pharmaceutically acceptable diluents, carriers and adjuvants (hereby incorporated by reference). Suitable dosages, formulations, administration routes, compositions, dosage forms, combinations with other therapeutic agents, pro-drug formulations are also provided in WO2007/031091.

Oligonucleotides or oligonucleotide conjugates of the invention may be mixed with pharmaceutically acceptable active or inert substances for the preparation of pharmaceutical compositions or formulations. Compositions and methods for the formulation of pharmaceutical compositions are dependent upon a number of criteria, including, but not limited to, route of administration, extent of disease, or dose to be administered.

In some embodiments, the oligonucleotide or oligonucleotide conjugate of the invention is a prodrug. In particular with respect to oligonucleotide conjugates the conjugate moiety is cleaved of the oligonucleotide once the prodrug is delivered to the site of action, e.g. the target cell.

Applications

The oligonucleotides of the invention may be utilized as research reagents for, for example, therapeutics and prophylaxis.

In research, such oligonucleotides may be used to specifically modulate the synthesis of UBE3A protein in cells (e.g. in vitro cell cultures) and experimental animals thereby facilitating functional analysis of the target or an appraisal of its usefulness as a target for therapeutic intervention. The target modulation is achieved by degrading or inhibiting a modulator of the gene or mRNA producing the protein.

For therapeutics, an animal or a human, suspected of having a disease or disorder, which can be treated by modulating the expression of UBE3A.

The invention provides methods for treating or preventing a disease, comprising administering a therapeutically or prophylactically effective amount of an oligonucleotide, an oligonucleotide conjugate or a pharmaceutical composition of the invention to a subject suffering from or susceptible to the disease.

The invention also relates to an oligonucleotide, a composition or a conjugate as defined herein for use as a medicament.

The oligonucleotide, oligonucleotide conjugate or a pharmaceutical composition according to the invention is typically administered in an effective amount.

The invention also provides for the use of the oligonucleotide or oligonucleotide conjugate of the invention as described for the manufacture of a medicament for the treatment of a disorder as referred to herein, or for a method of the treatment of as a disorder as referred to herein.

The disease or disorder, as referred to herein, is associated with expression of UBE3A. In some embodiments the disease or disorder may be associated with a mutation in the maternal UBE3A gene. In some embodiments, the target nucleic acid is a regulator of the paternal UBE3A gene.

The methods of the invention are preferably employed for treatment or prophylaxis against diseases caused by abnormal levels and/or activity of UBE3A. The disease may in particular be caused by reduced levels and/or activity of UBE3A protein.

The invention further relates to use of an oligonucleotide, oligonucleotide conjugate or a pharmaceutical composition as defined herein for the manufacture of a medicament for the treatment of abnormal levels and/or activity of UBE3A, in particular low levels and/or activity of UBE3A.

In one embodiment, the invention relates to oligonucleotides, oligonucleotide conjugates or pharmaceutical compositions for use in the treatment of Angelman syndrome.

Administration

The oligonucleotides or pharmaceutical compositions of the present invention may be administered topical (such as, to the skin, inhalation, ophthalmic or otic) or enteral (such as, orally or through the gastrointestinal tract) or parenteral (such as, intravenous, subcutaneous, intra-muscular, intracerebral, intracerebroventricular or intrathecal).

In a preferred embodiment the oligonucleotide or pharmaceutical compositions of the present invention are administered by a parenteral route including intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion, intrathecal or intracranial, e.g., intracerebral or intraventricular, administration. In one embodiment the active oligonucleotide or oligonucleotide conjugate is administered intracerebral or intracerebroventricular. In another embodiment the active oligonucleotide or oligonucleotide conjugate is administered intrathecal.

The invention also provides for the use of the oligonucleotide or oligonucleotide conjugate of the invention as described for the manufacture of a medicament wherein the medicament is in a dosage form for intrathecal administration.

The invention also provides for the use of the oligonucleotide or oligonucleotide conjugate of the invention as described for the manufacture of a medicament wherein the medicament is in a dosage form for intracerebral or intraventricular administration.

The invention also provides for the use of the oligonucleotide or oligonucleotide conjugate of the invention as described for the manufacture of a medicament wherein the medicament is in a dosage form for intracerebroventricular administration.

Combination Therapies

In some embodiments the oligonucleotide, oligonucleotide conjugate or pharmaceutical composition of the invention is for use in a combination treatment with another therapeutic agent. The therapeutic agent can for example be anticonvulsant medication.

EMBODIMENTS

The following embodiments of the present invention may be used in combination with any other embodiments described herein.

    • 1. An antisense oligonucleotide which comprises or consists of a contiguous nucleotide sequence of 10 to 30 nucleotides in length capable of inducing human paternal UBE3A expression, in particular in a neuronal cell.
    • 2. The oligonucleotide of embodiment 1, wherein the contiguous nucleotide sequence is at least 95% complementarity to the part of human SNHG14 long non-coding RNA which is downstream of SNORD109B corresponding to position 25278410 to 25419462 on chromosome 15.
    • 3. The oligonucleotide of embodiment 1 or 2, wherein the oligonucleotide is capable of hybridizing to a target nucleic acid of SEQ ID NO: 1 with a ΔG° below −10 kcal.
    • 4. The oligonucleotide of embodiment 1-3, wherein the contiguous nucleotide sequence is at least 95%, such as 98%, such as 100% complementarity to region of the target nucleic acid of SEQ ID NO: 1 and/or 2.
    • 5. The oligonucleotide of embodiment 1-3, wherein the contiguous nucleotide sequence is 100% complementary to a region of the target nucleic acid of position 1 to 55318 of SEQ ID NO: 1.
    • 6. The oligonucleotide of embodiment 1-4, wherein the contiguous nucleotide sequence is complementary to a sub-sequence of the target nucleic acid, wherein the subsequence is selected from the group consisting of the regions indicated in table 1 or 2.
    • 7. The oligonucleotide of embodiment 1-4, wherein the contiguous nucleotide sequence is at least 98% complementarity to the part of human SNHG14 long non-coding RNA which is antisense to the UBE3A pre-mRNA.
    • 8. The oligonucleotide of embodiments 1-4 or 7, wherein the oligonucleotide is capable of hybridizing to a target nucleic acid corresponding to position 55319 to 141053 of SEQ ID NO: 1, with a ΔG° below −10 kcal.
    • 9. The oligonucleotide of embodiments 1-4 or 7-8, wherein the contiguous nucleotide sequence is 100% complementary to a target nucleic acid of position 55319 to 141053 of SEQ ID NO: 1.
    • 10. The oligonucleotide of embodiment 1-8, wherein the target nucleic acid is RNA.
    • 11. The oligonucleotide of embodiment 10, wherein the RNA is a long non-coding RNA.
    • 12. The oligonucleotide of embodiment 1-11, wherein the contiguous nucleotide sequence comprises or consists of at least 10 contiguous nucleotides, particularly 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29 contiguous nucleotides.
    • 13. The oligonucleotide of embodiment 1-12, wherein the contiguous nucleotide sequence comprises or consists of from 12 to 22 nucleotides.
    • 14. The oligonucleotide of embodiment 13, wherein the contiguous nucleotide sequence comprises or consists of from 15-20 nucleotides.
    • 15. The oligonucleotide of embodiment 1-14, wherein the oligonucleotide comprises or consists of 10 to 35 nucleotides in length.
    • 16. The oligonucleotide of embodiment 15, wherein the oligonucleotide comprises or consists of 15 to 24 nucleotides in length.
    • 17. The oligonucleotide of embodiment 15 or 17, wherein the oligonucleotide comprises or consists of 17 to 22 nucleotides in length.
    • 18. The oligonucleotide of embodiment 1-17, wherein the oligonucleotide or contiguous nucleotide sequence is single stranded.
    • 19. The oligonucleotide of embodiment 1-18, wherein the contiguous nucleotide sequence is complementary to a sub-sequence of the target nucleic acid, selected from the group consisting of the regions indicated in table 1 or 2.
    • 20. The oligonucleotide of embodiment 1-18, wherein the contiguous nucleotide sequence is complementary to a sub-sequence of the target nucleic acid selected from the group consisting of position 1589-10889, 46089-53989 and 60789-62489 of SEQ ID NO: 1.
    • 21. The oligonucleotide of embodiment 1-18, wherein the contiguous nucleotide sequence is complementary to a sub-sequence of the target nucleic acid corresponding to positions 5218-5240 of SEQ ID NO: 1.
    • 22. The oligonucleotide of embodiment 1-18, wherein the contiguous nucleotide sequence is complementary to a sub-sequence of the target nucleic acid corresponding to positions 5782-5803 of SEQ ID NO: 1.
    • 23. The oligonucleotide of embodiment 1-18, wherein the contiguous nucleotide sequence is complementary to a sub-sequence of the target nucleic acid corresponding to positions 8113-8139 of SEQ ID NO: 1.
    • 24. The oligonucleotide of embodiment 1-18, wherein the contiguous nucleotide sequence is complementary to a sub-sequence of the target nucleic acid corresponding to positions: 9200-9250 of SEQ ID NO: 1.
    • 25. The oligonucleotide of embodiment 1-18, wherein the contiguous nucleotide sequence is complementary to a sub-sequence of the target nucleic acid corresponding to positions: 11505-11555 of SEQ ID NO: 1.
    • 26. The oligonucleotide of embodiment 1-18, wherein the contiguous nucleotide sequence is complementary to a sub-sequence of the target nucleic acid corresponding to positions 13223-13242 of SEQ ID NO: 1.
    • 27. The oligonucleotide of embodiment 1-18, wherein the contiguous nucleotide sequence is complementary to a sub-sequence of the target nucleic acid corresponding to positions 15100-15150 of SEQ ID NO: 1.
    • 28. The oligonucleotide of embodiment 1-18, wherein the contiguous nucleotide sequence is complementary to a sub-sequence of the target nucleic acid corresponding to positions 15113-15180 of SEQ ID NO: 1.
    • 29. The oligonucleotide of embodiment 1-18, wherein the contiguous nucleotide sequence is complementary to a sub-sequence of the target nucleic acid corresponding to positions 29635-29705 of SEQ ID NO: 1.
    • 30. The oligonucleotide of embodiment 1-18, wherein the contiguous nucleotide sequence is complementary to a sub-sequence of the target nucleic acid corresponding to positions 30590-30740 of SEQ ID NO: 1.
    • 31. The oligonucleotide of embodiment 1-18, wherein the contiguous nucleotide sequence is complementary to a sub-sequence of the target nucleic acid corresponding to positions 39800-39855 of SEQ ID NO: 1.
    • 32. The oligonucleotide of embodiment 1-18, wherein the contiguous nucleotide sequence is complementary to a sub-sequence of the target nucleic acid corresponding to positions 44435-44460 of SEQ ID NO: 1.
    • 33. The oligonucleotide of embodiment 1-18, wherein the contiguous nucleotide sequence is complementary to a sub-sequence of the target nucleic acid corresponding to positions 45245-45270 of SEQ ID NO: 1
    • 34. The oligonucleotide of embodiment 1-18, wherein the contiguous nucleotide sequence is complementary to a sub-sequence of the target nucleic acid to positions 46380-46430 of SEQ ID NO: 1.
    • 35. The oligonucleotide of embodiment 1-18, wherein the contiguous nucleotide sequence is complementary to a sub-sequence of the target nucleic acid corresponding to positions 68915-68940 of SEQ ID NO: 1.
    • 36. The oligonucleotide of embodiment 1-35, wherein the oligonucleotide is neither siRNA nor self-complementary.
    • 37. The oligonucleotide of embodiment 1-36, wherein the contiguous nucleotide sequence comprises or consists of a sequence selected from the group consisting of SEQ ID NO: 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 1819, 20, 21, 22, 23, 23, 24, 25, 26, 26, 27, 28, 29, 30, 31, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 44, 45, 45, 46, 47, 48, 49, 50, 51, 52, 53, 53, 54, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 79, 80, 81, 8283, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 95, 96, 96, 96, 97, 98, 99, 100, 101, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 639, 640, 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659, 660, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683, 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 700, 702, 703, 704, 705, 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 719, 720, 721, 722, 723, 724, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749, 750, 751, 752, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770, 772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 791, 792, 793, 794, 795, 796, 797, 798, 799, 800, 801, 802, 803, 804, 805, 806, 807, 808, 809, 810, 811, 812, 813, 814, 815, 816, 817 and 818.
    • 38. The oligonucleotide of embodiment 1-36, wherein the contiguous nucleotide sequence comprises or consists of a sequence selected from the group consisting of SEQ ID NO: 166, 167, 167 or 169 (see motif sequences listed in table 3 in the Examples section).
    • 39. The oligonucleotide of embodiment 1-36, wherein the contiguous nucleotide sequence comprises or consists of a sequence selected from the group consisting of SEQ ID NO: 570, 571, 572, 679, 680, 681, 682 and 683 (see motif sequences listed in table 3 in the Examples section).
    • 40. The oligonucleotide of embodiment 1-36, wherein the contiguous nucleotide sequence comprises or consists of a sequence selected from the group consisting of SEQ ID NO: 570, 571, 572, 679, 680, 681, 682 and 683 (see motif sequences listed in table 3 in the Examples section).
    • 41. The oligonucleotide of embodiment 1-36, wherein the contiguous nucleotide sequence comprises or consists of a sequence selected from the group consisting of SEQ ID NO: 35, 199 to 210 or SEQ ID NO: 582 to 584 (see motif sequences listed in table 3 in the Examples section).
    • 42. The oligonucleotide of embodiment 1-36, wherein the contiguous nucleotide sequence comprises or consists of a sequence selected from the group consisting of SEQ ID NO: 236, 237, 238, 239, 240 and 590 (see motif sequences listed in table 3 in the Examples section).
    • 43. The oligonucleotide of embodiment 1-36, wherein the contiguous nucleotide sequence comprises or consists of a sequence selected from the group consisting of SEQ ID NO: 221 to 225 or SEQ ID NO: 585 to 589 (see motif sequences listed in table 3 in the Examples section).
    • 44. The oligonucleotide of embodiment 1-36, wherein the contiguous nucleotide sequence comprises or consists of a sequence selected from the group consisting of SEQ ID NO: 241 or 591 (see motif sequences listed in table 3 in the Examples section).
    • 45. The oligonucleotide of embodiment 1-36, wherein the contiguous nucleotide sequence comprises or consists of a sequence selected from the group consisting of SEQ ID NO: 46-48, 285 to 305 or SEQ ID NO: 613 to 632 or SEQ ID NO: 721 to 807 (see motif sequences listed in table 3 in the Examples section).
    • 46. The oligonucleotide of embodiment 1-36, wherein the contiguous nucleotide sequence comprises or consists of a sequence selected from the group consisting of of SEQ ID NO: 331, 332, 638, 639, 640, 808, 809, 810, 811, 812, 813, 814 and 815 (see motif sequences listed in table 3 in the Examples section).
    • 47. The oligonucleotide of embodiment 1-36, wherein the contiguous nucleotide sequence comprises or consists of a sequence selected from the group consisting of SEQ ID NO: 409 to 411 or SEQ ID NO: 642 to 646 or SEQ ID NO: 816 to 818 (see motif sequences listed in table 3 in the Examples section).
    • 48. The oligonucleotide of embodiment 1-47, wherein the contiguous nucleotide sequence has zero to three mismatches compared to the target nucleic acid it is complementary to.
    • 49. The oligonucleotide of embodiment 48, wherein the contiguous nucleotide sequence has one mismatch compared to the target nucleic acid.
    • 50. The oligonucleotide of embodiment 48, wherein the contiguous nucleotide sequence has two mismatches compared to the target nucleic acid.
    • 51. The oligonucleotide of embodiment 48, wherein the contiguous nucleotide sequence is fully complementary to the target nucleic acid sequence.
    • 52. The oligonucleotide of embodiment 1-51, comprising one or more modified nucleosides.
    • 53. The oligonucleotide of embodiment 52, wherein the one or more modified nucleoside is a high-affinity modified nucleosides.
    • 54. The oligonucleotide of embodiment 52 or 53, wherein the one or more modified nucleoside is a 2′ sugar modified nucleoside.
    • 55. The oligonucleotide of embodiment 54, wherein the one or more 2′ sugar modified nucleoside is independently selected from the group consisting of 2′-O-alkyl-RNA, 2′-O-methyl-RNA, 2′-alkoxy-RNA, 2′-O-methoxyethyl-RNA, 2′-amino-DNA, 2′-fluoro-DNA, 2′-fluoro-ANA and LNA nucleosides.
    • 56. The oligonucleotide of embodiment 54, wherein the one or more modified nucleoside is a LNA nucleoside.
    • 57. The oligonucleotide of embodiment 56, wherein the modified LNA nucleoside is oxy-LNA.
    • 58. The oligonucleotide of embodiment 57, wherein the modified nucleoside is beta-D-oxy-LNA.
    • 59. The oligonucleotide of embodiment 57, wherein the modified nucleoside is alpha-L-oxy-LNA
    • 60. The oligonucleotide of embodiment 56, wherein the modified nucleoside is thio-LNA.
    • 61. The oligonucleotide of embodiment 56, wherein the modified nucleoside is amino-LNA.
    • 62. The oligonucleotide of embodiment 56, wherein the modified nucleoside is cET.
    • 63. The oligonucleotide of embodiment 56, wherein the modified nucleoside is ENA.
    • 64. The oligonucleotide of embodiment 56, wherein the modified LNA nucleoside is selected from beta-D-oxy-LNA, alpha-L-oxy-LNA, beta-D-amino-LNA, alpha-L-amino-LNA, beta-D-thio-LNA, alpha-L-thio-LNA, (S)cET, (R)cET beta-D-ENA and alpha-L-ENA.
    • 65. The oligonucleotide of any one of embodiments 1-64, wherein the oligonucleotide comprises at least one modified internucleoside linkage.
    • 66. The oligonucleotide of embodiment 65, wherein the modified internucleoside linkage is nuclease resistant.
    • 67. The oligonucleotide of embodiment 65 or 66, wherein at least 50% of the internucleoside linkages within the contiguous nucleotide sequence are phosphorothioate internucleoside linkages or boranophosphate internucleoside linkages.
    • 68. The oligonucleotide of embodiment 65 or 66, wherein all the internucleoside linkages within the contiguous nucleotide sequence are phosphorothioate internucleoside linkages.
    • 69. The oligonucleotide of embodiment 1-68, wherein the oligonucleotide is capable of recruiting RNase H.
    • 70. The oligonucleotide of embodiment 69, wherein the oligonucleotide is a gapmer.
    • 71. The oligonucleotide of embodiment 69 or 70, wherein the oligonucleotide is a gapmer of formula 5′-F-G-F′-3′, where region F and F′ independently comprise or consist of 1-7 modified nucleosides and G is a region between 6 and 16 nucleosides which are capable of recruiting RNaseH.
    • 72. The oligonucleotide of embodiment 71, wherein the modified nucleoside is a 2′ sugar modified nucleoside independently selected from the group consisting of 2′-O-alkyl-RNA, 2′-O-methyl-RNA, 2′-alkoxy-RNA, 2′-O-methoxyethyl-RNA, 2′-amino-DNA, 2′-fluoro-DNA, arabino nucleic acid (ANA), 2′-fluoro-ANA and LNA nucleosides.
    • 73. The oligonucleotide of embodiment 71 or 72, wherein one or more of the modified nucleosides in region F and F′ is a LNA nucleoside.
    • 74. The oligonucleotide of embodiment 73, wherein all the modified nucleosides in region F and F′ are LNA nucleosides.
    • 75. The oligonucleotide of embodiment 74, wherein region F and F′ consist of LNA nucleosides.
    • 76. The oligonucleotide of embodiment 73-75, wherein all the modified nucleosides in region F and F′ are oxy-LNA nucleosides.
    • 77. The oligonucleotide of embodiment 73, wherein at least one of region F or F′ further comprises at least one 2′ substituted modified nucleoside independently selected from the group consisting of 2′-O-alkyl-RNA, 2′-O-methyl-RNA, 2′-alkoxy-RNA, 2′-O-methoxyethyl-RNA, 2′-amino-DNA and 2′-fluoro-DNA.
    • 78. The oligonucleotide of embodiment 73-77, wherein the RNaseH recruiting nucleosides in region G are independently selected from DNA, alpha-L-LNA, C4′ alkylated DNA, ANA and 2′F-ANA and UNA.
    • 79. The oligonucleotide of embodiment 78, wherein the nucleosides in region G is DNA and/or alpha-L-LNA nucleosides.
    • 80. The oligonucleotide of embodiment 78 or 79, wherein region G consists of at least 75% DNA nucleosides.
    • 81. The oligonucleotide of embodiment 1-80, wherein the oligonucleotide is capable of increasing the expression of UBE3A by at least 30% compared to a control.
    • 82. The oligonucleotide of embodiment 1-81, wherein the level of the SNHG14 transcript downstream of SNORD109B is reduced by at least 20% compared to a control.
    • 83. The oligonucleotide of embodiment 1-82, wherein the expression of SNORD115 is not significantly affected compared to a control.
    • 84. The oligonucleotide of embodiment 1-83, wherein the oligonucleotide is selected from CMP ID NO: 4_1 to 678_1.
    • 85. The oligonucleotide of embodiment 1-83, wherein the oligonucleotide is selected from the group consisting of CMP ID NO: 4_1, 4_2, 5_1, 5_2, 6_1, 6_2, 7_1, 7_2, 8_1, 9_1, 101, 111, 11_2, 121, 12_2, 13_1, 13_2, 14_1, 15_1, 16_1, 17_1, 17_2, 18_1, 18_2, 19_1, 19_2, 20_1, 21_1, 22_1, 23_1, 23_2, 24_1, 25_1, 26_1, 26_2, 27_1, 28_1, 28_2, 29_1, 29_2, 30_1, 31_1, 31_2, 32_1, 33_1, 34_1, 34_2, 34_3, 34_4, 34_5, 34_6, 34_7, 35_1, 35_2, 36_1, 37_1, 38_1, 38_2, 38_3, 38_4, 38_5, 38_6, 39_1, 39_2, 39_3, 39_4, 39_5, 40_1, 40_2, 40_3, 40_4, 40_5, 40_6, 40_7, 40_8, 41_1, 42_1, 43_1, 44_1, 44_2, 45_1, 4_2, 46_1, 47_1, 48_1, 48_2, 48_3, 48_4, 48_5, 48_6, 48_7, 49_1, 50_1, 51_1, 52_1, 53_1, 53_2, 54_1, 54_2, 54_3, 55_1, 55_2, 56_1, 57_1, 58_1, 58_2, 58_3, 59_1, 59_2, 60_1, 60_2, 60_3, 61_1, 62_1, 63_1, 64_1, 64_2, 65_1, 66_1, 67_1, 68_1, 69_1, 69_2, 69_3, 70_1, 70_2, 70_3, 71_1, 72_1, 72_2, 73_1, 73_2, 73_3, 74_1, 74_2, 75_1, 75_2, 76_1, 77_1, 77_2, 77_3, 78_1, 79_1, 79_2, 79_3, 80_1, 80_2, 80_3, 81_1, 82_1, 82_2, 83_1, 83_2, 84_1, 84_2, 85_1, 85_2, 86_1, 87_1, 88_1, 88_2, 89_1, 90_1, 91_1, 92_1, 93_1, 94_1, 95_1, 95_2, 961, 96_2, 96_3, 97_1, 97_2, 97_3, 97_4, 98_1, 98_2, 98_3, 99_1, 99_2, 99_3, 99_4, 100_1, 100_2, 100_3, 101_1, 101_2, 101_3, 101_4, 102_1, 102_2, 102_3, 102_4, 103_1, 103_2, 103_3, 103_4, 104_1, 104_2, 104_3, 105_1, 105_2, 105_3, 105_4, 106_1, 106_2, 106_3, 106_4, 107_1, 107_2, 107_3, 107_4, 108_1, 108_2, 108_3, 108_4, 109_1, 109_2, 109_3, 109_4, 110_1, 110_2, 111_1, 111_2, 111_3, 112_1, 112_2, 113_1, 114_1, 115_1, 116_1, 117_1, 118_1, 119_1, 120_1, 120_2, 121_1, 122_1, 123_1, 124_1, 125_1, 126_1, 126_2, 127_1, 128_1, 128_2, 128_3, 128_4, 129_1, 129_2, 130_1, 131_1, 132_1, 132_2, 132_3, 133_1, 133_2, 133_3, 133_4, 134_1, 134_2, 135_1, 135_2, 136_1, 137_1, 138_1, 139_1, 140_1, 141_1, 142_1, 143_1, 144_1, 145_1, 145_2, 146_1, 146_2, 147_1, 148_1, 149_1, 150_1, 150_2, 151_1, 152_1, 153_1, 154_1, 155_1, 156_1, 157_1, 158_1, 159_1, 160_1, 161_1, 162_1, 163_1, 164_1, 165_1, 166_1, 167_1, 168_1, 169_1, 169_10, 169_11, 169_12, 169_13, 169_14, 169_15, 169_16, 169_17, 169_18, 169_19, 169_2, 169_20, 169_21, 169_22, 169_23, 169_24, 169_25, 169_26, 169_27, 169_28, 169_29, 169_3, 169_30, 169_31, 169_32, 169_33, 169_34, 169_35, 169_36, 169_37, 169_38, 169_39, 169_4, 169_40, 169_41, 169_42, 169_43, 169_44, 169_45, 169_46, 169_47, 169_48, 169_49, 169_5, 169_50, 169_51, 169_52, 169_53, 169_54, 169_55, 169_56, 169_57, 169_6, 169_7, 169_8, 169_9, 169_58, 169_59, 169_60, 169_61, 169_62, 170_1, 171_1, 172_1, 173_1, 174_1, 175_1, 176_1, 177_1, 178_1, 179_1, 180_1, 181_1, 182_1, 183_1, 184_1, 185_1, 186_1, 187_1, 188_1, 189_1, 190_1, 191_1, 192_1, 193_1, 194_1, 195_1, 196_1, 197_1, 198_1, 199_1, 200_1, 201_1, 202_1, 203_1, 204_1, 205_1, 206_1, 207_1, 208_1, 208_2, 208_3, 208_4, 208_5, 208_6, 208_7, 209_1, 209_10, 209_2, 209_3, 209_4, 209_5, 209_6, 209_7, 209_8, 209_9, 210_1, 211_1, 212_1, 213_1, 214_1, 215_1, 216_1, 217_1, 218_1, 219_1, 220_1, 221_1, 222_1, 223_1, 224_1, 225_1, 226_1, 227_1, 228_1, 229_1, 230_1, 231_1, 232_1, 233_1, 234_1, 235_1, 236_1, 236_10, 236_11, 236_12, 236_13, 236_14, 236_15, 236_16, 236_2, 236_3, 236_4, 236_5, 236_6, 236_7, 236_8, 236_9, 236_17, 236_18, 236_19, 236_20, 236_21, 237_1, 237_10, 237_11, 237_12, 237_13, 237_14, 237_15, 237_16, 237_2, 237_3, 237_4, 237_5, 237_6, 237_7, 237_8, 237_9, 237_17, 237_18, 237_19, 237_20, 237_21, 238_1, 239_1, 239_10, 239_11, 239_12, 239_13, 239_14, 239_15, 239_16, 239_2, 239_3, 239_4, 239_5, 239_6, 239_7, 239_8, 239_9, 239_17, 239_18, 239_19, 239_20, 239_21, 240_1, 241_1, 241_10, 241_2, 241_3, 241_4, 241_5, 241_6, 241_7, 241_8, 241_9, 241_11, 241_12, 241_13, 241_14, 241_15, 242_1, 243_1, 244_1, 244_2, 244_3, 244_4, 244_5, 245_1, 246_1, 247_1, 248_1, 249_1, 250_1, 251_1, 252_1, 253_1, 254_1, 255_1, 256_1, 257_1, 258_1, 259_1, 260_1, 261_1, 262_1, 263_1, 264_1, 265_1, 266_1, 267_1, 268_1, 269_1, 270_1, 271_1, 272_1, 273_1, 274_1, 275_1, 276_1, 277_1, 278_1, 279_1, 280_1, 281_1, 282_1, 283_1, 284_1, 285_1, 285_2, 285_3, 285_4, 285_5, 285_6, 285_7, 285_8, 285_9, 285_10, 285_11, 286_1, 287_1, 288_1, 289_1, 290_1, 291_1, 292_1, 293_1, 294_1, 295_1, 296_1, 297_1, 298_1, 299_1, 300_1, 301_1, 302_1, 303_1, 304_1, 304_10, 304_2, 304_3, 304_4, 304_5, 304_6, 304_7, 304_8, 304_9, 304_11, 304_12, 304_13, 304_14, 304_15, 305_1, 306_1, 307_1, 308_1, 309_1, 310_1, 311_1, 312_1, 313_1, 314_1, 315_1, 316_1, 317_1, 318_1, 319_1, 320_1, 321_1, 322_1, 323_1, 324_1, 325_1, 326_1, 327_1, 328_1, 329_1, 330_1, 331_1, 332_1, 333_1, 334_1, 335_1, 336_1, 337_1, 338_1, 339_1, 340_1, 341_1, 342_1, 343_1, 344_1, 345_1, 346_1, 347_1, 348_1, 349_1, 350_1, 351_1, 352_1, 353_1, 354_1, 355_1, 356_1, 357_1, 358_1, 359_1, 360_1, 361_1, 361_10, 361_2, 361_3, 361_4, 361_5, 361_6, 361_7, 361_8, 361_9, 362_1, 362_10, 362_2, 362_3, 362_4, 362_5, 362_6, 362_7, 362_8, 362_9, 363_1, 364_1, 365_1, 366_1, 367_1, 368_1, 369_1, 370_1, 371_1, 372_1, 373_1, 374_1, 375_1, 376_1, 377_1, 378_1, 379_1, 380_1, 381_1, 382_1, 383_1, 384_1, 385_1, 386_1, 387_1, 388_1, 389_1, 390_1, 391_1, 392_1, 393_1, 394_1, 395_1, 396_1, 397_1, 398_1, 399_1, 400_1, 401_1, 402_1, 403_1, 404_1, 405_1, 406_1, 407_1, 408_1, 409_1, 410_1, 411_1, 412_1, 413_1, 414_1, 415_1, 416_1, 417_1, 418_1, 419_1, 420_1, 421_1, 422_1, 423_1, 424_1, 425_1, 425_10, 425_2, 425_3, 425_4, 425_5425_6425__7425_8425_942614271428_1, 429_1, 430_1, 431_1, 432_1, 433_1, 434_1, 435_1, 436_1, 437_1, 438_1, 439_1, 440_1, 441_1, 442_1, 443_1, 444_1, 445_1, 446_1, 447_1, 448_1, 449_1, 450_1, 451_1, 452_1, 453_1, 454_1, 455_1, 456_1, 457_1, 458_1, 459_1, 460_1, 461_1, 462_1, 463_1, 464_1, 465_1, 466_1, 467_1, 468_1, 469_1, 470_1, 471_1, 472_1, 473_1, 474_1, 475_1, 476_1, 477_1, 478_1, 479_1, 480_1, 481_1, 482_1, 483_1, 484_1, 485_1, 486_1, 487_1, 488_1, 489_1, 490_1, 491_1, 492_1, 493_1, 494_1, 495_1, 496_1, 497_1, 498_1, 499_1, 500_1, 501_1, 502_1, 503_1, 504_1, 505_1, 506_1, 507_1, 508_1, 509_1, 510_1, 511_1, 512_1, 513_1, 514_1, 515_1, 516_1, 517_1, 518_1, 519_1, 520_1, 521_1, 522_1, 523_1, 524_1, 525_1, 526_1, 527_1, 528_1, 529_1, 530_1, 531_1, 532_1, 533_1, 534_1, 535_1, 536_1, 537_1, 538_1, 539_1, 540_1, 541_1, 542_1, 543_1, 544_1, 545_1, 546_1, 547_1, 548_1, 549_1, 550_1, 551_1, 552_1, 553_1, 554_1, 555_1, 556_1, 557_1, 558_1, 559_1, 560_1, 561_1, 562_1, 563_1, 564_1, 565_1, 566_1, 567_1, 568_1, 569_1, 570_1, 570_2, 570_3, 570_4, 570_5, 570_6, 570_7, 570_8, 570_9, 570_10, 570_11, 570_12, 570_13, 570_14, 571_1, 571_2, 571_3, 571_4, 571_5, 571_6, 571_7, 571_8, 571_9, 571_10, 571_11, 571_12, 571_13, 571_14, 572_1, 572_2, 572_3, 572_4, 572_5, 572_6, 572_7, 572_8, 572_9, 572_10, 572_11, 572_12, 572_13, 572_14, 573_1, 573_2, 573_3, 573_4, 573_5, 573_6, 573_7, 573_8, 573_9, 573_10, 573_11, 573_12, 573_13, 573_14, 574_1, 574_2, 574_3, 574_4, 574_5, 574_6, 574_7, 574_8, 574_9, 574_10, 574_11, 574_12, 574_13, 574_14, 575_1, 575_2, 575_3, 575_4, 575_5, 575_6, 575_7, 575_8, 575_9, 575_10, 575_11, 575_12, 575_13, 575_14, 576_1, 576_2, 576_3, 576_4, 576_5, 576_6, 576_7, 576_8, 576_9, 576_10, 576_11, 576_12, 576_13, 576_14, 577_1, 577_2, 577_3, 577_4, 577_5, 577_6, 577_7, 577_8, 577_9, 577_10, 577_11, 577_12, 577_13, 577_14, 578_1, 578_2, 578_3, 578_4, 578_5, 578_6, 578_7, 578_8, 578_9, 579_1, 579_2, 579_3, 579_4, 579_5, 579_6, 579_7, 579_8, 579_9, 580_1, 580_2, 580_3, 580_4, 580_5, 580_6, 580_7, 580_8, 580_9, 581_1, 581_2, 581_3, 581_4, 581_5, 581_6, 581_7, 581_8, 581_9, 582_1, 582_2, 582_3, 582_4, 582_5, 582_6, 582_7, 582_8, 582_9, 583_1, 583_2, 583_3, 583_4, 583_5, 583_6, 583_7, 583_8, 583_9, 584_1, 584_2, 584_3, 584_4, 584_5, 584_6, 584_7, 584_8, 585_1, 585_2, 585_3, 585_4, 585_5, 585_6, 585_7, 585_8, 585_9, 585_10, 585_11, 585_12, 585_13, 585_14, 586_1, 586_2, 586_3, 586_4, 586_5, 586_6, 586_7, 586_8, 586_9, 586_10, 586_11, 586_12, 586_13, 586_14, 587_1, 587_2, 587_3, 587_4, 587_5, 587_6, 587_7, 587_8, 587_9, 587_10, 587_11, 587_12, 587_13, 587_14, 588_1, 588_2, 588_3, 588_4, 588_5, 588_6, 588_7, 588_8, 588_9, 588_10, 588_11, 588_12, 588_13, 588_14, 589_1, 589_2, 589_3, 589_4, 589_5, 589_6, 589_7, 589_8, 589_9, 589_10, 589_11, 589_12, 589_13, 589_14, 590_1, 590_10, 590_11, 590_12, 590_13, 590_14, 590_15, 590_2, 590_3, 590_4, 590_5, 590_6, 590_7, 590_8, 590_9, 590_16, 590_17, 590_18, 590_19, 590_20, 591_1, 591_2, 592_1, 592_2, 592_3, 592_4, 592_5, 592_6, 592_7, 592_8, 592_9, 592_10, 592_11, 592_12, 592_13, 592_14, 593_1, 593_2, 593_3, 593_4, 594_1, 594_2, 594_3, 594_4, 595_1, 595_2, 595_3, 595_4, 596_1, 596_2, 596_3, 596_4, 597_1, 597_2, 597_3, 597_4, 598_1, 598_2, 598_3, 598_4, 599_1, 599_2, 599_3, 599_4, 600_1, 600_2, 600_3, 600_4, 601_1, 601_2, 601_3, 601_4, 602_1, 602_2, 602_3, 602_4, 603_1, 603_2, 603_3, 603_4, 604_1, 604_2, 604_3, 604_4, 605_1, 605_2, 605_3, 605_4, 606_1, 606_2, 606_3, 606_4, 607_1, 607_2, 607_3, 607_4, 608_1, 608_2, 608_3, 608_4, 608_5, 608_6, 608_7, 608_8, 608_9, 609_1, 609_2, 609_3, 609_4, 609_5, 609_6, 609_7, 609_8, 609_9, 610_1, 610_2, 610_3, 610_4, 610_5, 610_6, 610_7, 610_8, 610_9, 611_1, 611_2, 611_3, 611_4, 611_5, 611_6, 611_7, 611_8, 611_9, 612_1, 612_2, 612_3, 612_4, 612_5, 612_6, 612_7, 612_8, 612_9, 613_1, 613_2, 613_3, 613_4, 613_5, 613_6, 613_7, 613_8, 613_9, 613_10, 614_1, 614_2, 614_3, 614_4, 614_5, 614_6, 614_7, 614_8, 614_9, 614_10, 615_1, 615_2, 615_3, 615_4, 615_5, 615_6, 615_7, 615_8, 615_9, 615_10, 616_1, 616_2, 616_3, 616_4, 616_5, 616_6, 616_7, 616_8, 616_9, 616_10, 617_1, 617_2, 617_3, 617_4, 617_5, 617_6, 617_7, 617_8, 617_9, 617_10, 618_1, 618_2, 618_3, 618_4, 618_5, 618_6, 618_7, 618_8, 618_9, 618_10, 619_1, 619_2, 619_3, 619_4, 619_5, 619_6, 619_7, 619_8, 619_9, 619_10, 620_1, 620_2, 620_3, 620_4, 620_5, 620_6, 620_7, 620_8, 620_9, 620_10, 621_1, 621_2, 621_3, 621_4, 621_5, 621_6, 621_7, 621_8, 621_9, 621_10, 621_11, 622_1, 622_2, 622_3, 622_4, 622_5, 622_6, 622_7, 622_8, 622_9, 622_10, 623_1, 623_2, 623_3, 623_4, 623_5, 623_6, 623_7, 623_8, 623_9, 623_10, 624_1, 624_2, 624_3, 624_4, 624_5, 624_6, 624_7, 624_8, 624_9, 624_10, 625_1, 625_2, 625_3, 625_4, 625_5, 625_6, 625_7, 625_8, 625_9, 625_10, 625_11, 625_12, 625_13, 625_14, 626_1, 626_2, 626_3, 626_4, 626_5, 626_6, 626_7, 626_8, 626_9, 626_10, 626_11, 626_12, 626_13, 626_14, 627_1, 627_2, 627_3, 627_4, 627_5, 627_6, 627_7, 627_8, 627_9, 627_10, 627_11, 627_12, 627_13, 627_14, 628_1, 628_2, 628_3, 628_4, 628_5, 628_6, 628_7, 628_8, 628_9, 628_10, 628_11, 628_12, 628_13, 628_14, 629_1, 629_10, 629_11, 629_2, 629_3, 629_4, 629_5, 629_6, 629_7, 629_8, 629_9, 629_12, 629_13, 629_14, 629_15, 629_16, 630_1, 630_2, 630_3, 631_1, 631_10, 631_2, 631_3, 631_4, 631_5, 631_6, 631_7, 631_8, 631_9, 631_11, 631_12, 631_13, 631_14, 631_15, 632_1, 632_2, 632_3, 632_4, 632_5, 632_6, 632_7, 632_8, 632_9, 632_10, 632_11, 632_12, 632_13, 632_14, 633_1, 633_2, 633_3, 633_4, 633_5, 633_6, 633_7, 633_8, 633_9, 634_1, 634_2, 634_3, 634_4, 634_5, 634_6, 634_7, 634_8, 634_9, 635_1, 635_2, 635_3, 635_4, 635_5, 635_6, 635_7, 635_8, 635_9, 636_1, 636_2, 636_3, 636_4, 636_5, 636_6, 636_7, 636_8, 636_9, 637_1, 637_2, 637_3, 637_4, 637_5, 637_6, 637_7, 637_8, 637_9, 638_1, 638_2, 638_3, 638_4, 638_5, 638_6, 638_7, 638_8, 638_9, 638_10, 638_11, 638_12, 638_13, 638_14, 639_1, 639_2, 639_3, 639_4, 639_5, 639_6, 639_7, 639_8, 639_9, 639_10, 639_11, 639_12, 639_13, 639_14, 640_1, 640_2, 640_3, 640_4, 640_5, 640_6, 640_7, 640_8, 640_9, 640_10, 640_11, 640_12, 640_13, 640_14, 641_1, 641_2, 641_3, 641_4, 641_5, 641_6, 641_7, 641_8, 641_9, 642_1, 642_10, 642_11, 642_12, 642_13, 642_14, 642_15, 642_16, 642_17, 642_2, 642_3, 642_4, 642_5, 642_6, 642_7, 642_8, 642_9, 642_18, 642_19, 642_20, 642_21, 642_22, 643_1, 644_1, 644_2, 644_3, 644_4, 644_5, 644_6, 645_1, 645_2, 645_3, 645_4, 645_5, 645_6, 645_7, 645_8, 645_9, 645_10, 646_1, 646_10, 646_11, 646_12, 646_13, 646_14, 646_15, 646_16, 646_17, 646_18, 646_19, 646_2, 646_3, 646_4, 646_5, 646_6, 646_7, 646_8, 646_9, 646_20, 646_21, 646_22, 646_23, 646_24, 647_1, 648_1, 649_1, 650_1, 651_1, 652_1, 653_1, 654_1, 655_1, 656_1, 657_1, 658_1, 659_1, 660_1, 661_1, 662_1, 663_1, 664_1, 665_1, 666_1, 667_1, 668_1, 669_1, 670_1, 671_1, 672_1, 673_1, 674_1, 675_1, 676_1, 677_1, 678_1, 679_1, 679_2, 679_3, 679_4, 679_5, 680_1, 680_2, 680_3, 680_4, 680_5, 681_1, 681_2, 681_3, 681_4, 681_5, 682_1, 682_2, 682_3, 682_4, 682_5, 683_1, 683_2, 683_3, 683_4, 683_5, 684_1, 684_2, 684_3, 684_4, 684_5, 685_1, 685_2, 685_3, 685_4, 685_5, 686_1, 686_2, 686_3, 686_4, 686_5, 687_1, 687_2, 687_3, 687_4, 687_5, 688_1, 688_2, 688_3, 688_4, 688_5, 689_1, 689_2, 689_3, 689_4, 689_5, 690_1, 690_2, 690_3, 690_4, 690_5, 691_1, 691_2, 692_1, 692_2, 692_3, 692_4, 692_5, 693_1, 693_2, 693_3, 693_4, 693_5, 694_1, 694_2, 694_3, 694_4, 694_5, 695_1, 695_2, 695_3, 695_4, 695_5, 696_1, 696_2, 696_3, 696_4, 696_5, 697_1, 697_2, 697_3, 697_4, 697_5, 698_1, 698_2, 698_3, 698_4, 698_5, 699_1, 699_2, 699_3, 699_4, 699_5, 700_1, 700_2, 700_3, 700_4, 700_5, 701_1, 701_2, 701_3, 701_4, 701_5, 702_1, 702_2, 702_3, 702_4, 702_5, 703_1, 703_2, 703_3, 703_4, 703_5, 704_1, 704_2, 704_3, 704_4, 704_5, 705_1, 705_2, 705_3, 705_4, 705_5, 706_1, 706_2, 706_3, 706_4, 706_5, 707_1, 707_2, 707_3, 707_4, 707_5, 708_1, 708_2, 708_3, 708_4, 708_5, 709_1, 709_2, 709_3, 709_4, 709_5, 710_1, 710_2, 710_3, 710_4, 710_5, 711_1, 711_2, 711_3, 711_4, 711_5, 712_1, 712_2, 712_3, 712_4, 712_5, 713_1, 713_2, 713_3, 713_4, 713_5, 714_1, 714_2, 714_3, 714_4, 714_5, 715_1, 715_2, 715_3, 715_4, 715_5, 716_1, 716_2, 716_3, 716_4, 716_5, 717_1, 717_2, 717_3, 717_4, 717_5, 718_1, 718_2, 719_1, 719_2, 719_3, 719_4, 719_5, 720_1, 720_2, 720_3, 720_4, 720_5, 721_1, 721_2, 721_3, 721_4, 721_5, 722_1, 722_2, 722_3, 722_4, 722_5, 723_1, 723_2, 723_3, 723_4, 723_5, 724_1, 724_2, 724_3, 724_4, 724_5, 725_1, 725_2, 725_3, 725_4, 725_5, 726_1, 726_2, 726_3, 726_4, 726_5, 727_1, 727_2, 727_3, 727_4, 727_5, 728_1, 728_2, 728_3, 728_4, 728_5, 729_1, 729_2, 729_3, 729_4, 729_5, 730_1, 730_2, 730_3, 730_4, 730_5, 731_1, 731_2, 731_3, 731_4, 731_5, 732_1, 732_2, 732_3, 732_4, 732_5, 733_1, 733_2, 733_3, 733_4, 733_5, 734_1, 734_2, 373_4, 34_4, 734_5, 735_1, 735_2, 735_3, 735_4, 735_5, 736_1, 736_2, 736_3, 736_4, 736_5, 737_1, 737_2, 737_3, 737_4, 737_5, 738_1, 738_2, 738_3, 738_4, 738_5, 738_6, 739_1, 739_2, 739_3, 739_4, 739_5, 740_1, 740_2, 740_3, 740_4, 740_5, 741_1, 741_2, 741_3, 741_4, 741_5, 742_1, 742_2, 742_3, 743_1, 743_2, 743_3, 743_4, 743_5, 744_1, 744_2, 744_3, 744_4, 744_5, 745_1, 745_2, 745_3, 745_4, 745_5, 746_1, 746_2, 746_3, 747_1, 747_2, 747_3, 747_4, 747_5, 748_1, 748_2, 748_3, 748_4, 748_5, 749_1, 749_2, 749_3, 749_4, 749_5, 750_1, 750_2, 750_3, 750_4, 7_1, 751_2, 751_3, 751_4, 751_5, 752_1, 752_2, 752_3, 752_4, 752_5, 753_1, 753_2, 753_3, 753_4, 753_5, 754_1, 754_2, 754_3, 754_4, 754_5, 755_1, 755_2, 755_3, 755_4, 755_5, 756_1, 756_2, 756_3, 756_4, 756_5, 757_1, 757_2, 757_3, 757_4, 757_5, 758_1, 758_2, 758_3, 758_4, 758_5, 759_1, 759_2, 759_3, 759_4, 759_5, 760_1, 760_2, 760_3, 760_4, 760_5, 761_1, 761_2, 761_3, 761_4, 761_5, 762_1, 762_2, 762_3, 762_4, 762_5, 763_1, 763_2, 763_3, 763_4, 763_5, 764_1, 764_2, 764_3, 764_4, 764_5, 765_1, 765_2, 765_3, 765_4, 765_5, 766_1, 766_2, 766_3, 766_4, 766_5, 767_1, 767_2, 767_3, 767_4, 767_5, 768_1, 768_2, 768_3, 768_4, 768_5, 769_1, 769_2, 769_3, 769_4, 769_5, 770_1, 770_2, 770_3, 770_4, 770_5, 771_1, 771_2, 771_3, 771_4, 771_5, 772_1, 772_2, 772_3, 772_4, 772_5, 773_1, 773_2, 773_3, 773_4, 773_5, 774_1, 774_2, 774_3, 774_4, 774_5, 775_1, 775_2, 775_3, 775_4, 775_5, 776_1, 776_2, 776_3, 776_4, 776_5, 777_1, 777_2, 777_3, 777_4, 777_5, 778_1, 778_2, 778_3, 778_4, 778_5, 779_1, 779_2, 779_3, 779_4, 779_5, 780_1, 780_2, 780_3, 780_4, 780_5, 781_1, 782_1, 782_2, 782_3, 782_4, 782_5, 783_1, 783_2, 783_3, 783_5, 784_1, 784_2, 784_3, 784_4, 784_5, 785_1, 786_1, 786_2, 786_3, 786_4, 786_5, 787_1, 787_2, 787_3, 787_4, 787_5, 788_1, 788_2, 788_3, 788_4, 788_5, 789_1, 789_2, 789_3, 789_4, 789_5, 790_1, 790_2, 790_3, 790_4, 790_5, 791_1, 791_2, 791_3, 791_4, 791_5, 792_1, 792_2, 792_3, 792_4, 792_5, 793_1, 793_2, 793_3, 793_4, 793_5, 794_1, 794_2, 794_3, 4, 7_4, 794_5, 795_1, 795_2, 795_3, 795_4, 795_5, 796_1, 796_2, 796_3, 796_4, 796_5, 797_1, 797_2, 797_3, 797_4, 797_5, 798_1, 798_2, 798_3, 798_4, 798_5, 799_1, 799_2, 799_3, 799_4, 799_5, 800_1, 800_2, 800_3, 800_4, 800_5, 801_1, 801_2, 801_3, 801_4, 801_5, 802_1, 802_2, 802_3, 802_4, 802_5, 803_1, 803_2, 803_3, 803_4, 803_5, 804_1, 804_2, 804_3, 804_4, 804_5, 805_1, 805_2, 805_3, 805_4, 805_5, 806_1, 806_2, 806_3, 806_4, 806_5, 807_1, 807_2, 807_3, 807_4, 807_5, 808_1, 808_2, 808_3, 808_4, 808_5, 809_1, 809_2, 809_3, 809_4, 809_5, 810_1, 810_2, 810_3, 810_4, 810_5, 811_1, 811_2, 811_3, 811_4, 811_5, 812_1, 812_2, 812_3, 812_4, 812_5, 813_1, 813_2, 813_3, 813_4, 813_5, 814_1, 814_2, 814_3, 814_4, 814_5, 815_1, 815_2, 815_3, 15_4, 815_5, 816_1, 816_2, 816_3, 816_4, 816_5, 816_6, 817_1 and 818_1.
    • 86. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from CMP-ID-NO: 155_1 or 165_1.
    • 87. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from the group consisting of CMP-ID-NO 169_52, 169_50 or 169_56.
    • 88. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from the group consisting of CMP-ID-NO: 172_1, 272_1, 572_7, 572_6 or 572_5.
    • 89. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from CMP-ID-NO: 175_1.
    • 90. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from CMP-ID-NO: 178_1.
    • 91. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from CMP-ID-NO: 573_8, 186_1 or 187_1.
    • 92. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from CMP-ID-NO: 186_1.
    • 93. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from the group consisting of CMP-ID-NO: 200_1, 204_1, 206_1, 35_2 or 209_1.
    • 94. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from the group consisting of CMP-ID-NO: 585_1, 585_8, 586_9, 586_5, 586_8, 586_4 or 586_6.
    • 95. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from CMP-ID-NO: 233_1.
    • 96. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from CMP-ID-NO: 237_8 or 590_13.
    • 97. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from CMP-ID-NO: 220_1.
    • 98. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from the group consisting of CMP-ID-NO: 591_1, 592_2, 592_4 or 241_9.
    • 99. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from the group consisting of CMP-ID-NO: 597_4, 598_4, 39_1 or 602_1.
    • 100. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from CMP-ID-NO: 39_1.
    • 101. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from CMP-ID-NO: 611_7.
    • 102. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from the group consisting of CMP-ID-NO: 271_1 or 278_1.
    • 103. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from the group consisting of CMP-ID-NO: 616_4, 621_2, 621_1, 622_3, 622_5, 622_4, 624_3, 624_5, 287_1, 625_6, 626_7, 626_8, 626_9, 48_1, 631_6, 631_1, 303_1, 304_6 or 304_10.
    • 104. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from CMP-ID-NO: 636_8.
    • 105. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from the group consisting of CMP-ID-NO: 638_8, 639_5, 331_1 or 640_4.
    • 106. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from the group consisting of CMP-ID-NO: 359_1, 361_1, 361_5, 362_1 or 641_5.
    • 107. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from the group consisting of CMP-ID-NO: 378_1, 379_1 or 399_1.
    • 108. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from the group consisting of CMP-ID-NO: 403_1, 405_1, 642_12, 642_13, 644_3 or 646_16.
    • 109. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from CMP-ID-NO: 85_1 or 425_5.
    • 110. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from CMP-ID-NO: 116_1.
    • 111. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from CMP-ID-NO: 123_1 or 124_1.
    • 112. The oligonucleotide of embodiment 85, wherein the oligonucleotide is selected from CMP-ID-NO: 126_2.
    • 113. A conjugate comprising the oligonucleotide according to any one of claims 1-112, and at least one conjugate moiety covalently attached to said oligonucleotide.
    • 114. The oligonucleotide conjugate of embodiment 113, wherein the conjugate moiety is selected from carbohydrates, cell surface receptor ligands, drug substances, hormones, lipophilic substances, polymers, proteins, peptides, toxins, vitamins, viral proteins or combinations thereof.
    • 115. The oligonucleotide conjugate of embodiment 113 or 114, wherein the conjugate moiety is an antibody or antibody fragment.
    • 116. The oligonucleotide conjugate of embodiment 115, wherein the antibody or antibody fragment has affinity to the transferrin receptor.
    • 117. The oligonucleotide conjugate of embodiment 113-115, comprising a linker which is positioned between the oligonucleotide and the conjugate moiety.
    • 118. The oligonucleotide conjugate of embodiment 117, wherein the linker is a physiologically labile linker.
    • 119. The oligonucleotide conjugate of embodiment 118, wherein the physiologically labile linker is nuclease susceptible linker.
    • 120. The oligonucleotide conjugate of embodiment 118 or 119, wherein the oligonucleotide has the formula D-F-G-F′ or F-G-F′-D′, wherein F, F′ and G are as defined in embodiments 73-80 and D or D′ comprises 1, 2 or 3 DNA nucleosides with phosphorothioate internucleoside linkages.
    • 121. The oligonucleotide conjugate of embodiment 113-120, which display improved uptake into the brain of the conjugate oligonucleotide as compared to an unconjugated oligonucleotide.
    • 122. A pharmaceutical composition comprising the oligonucleotide of embodiment 1-112 or a conjugate of embodiment 113-121 and a pharmaceutically acceptable diluent, carrier, salt and/or adjuvant.
    • 123. A method for manufacturing the oligonucleotide of embodiment 1-112, comprising reacting nucleotide units thereby forming covalently linked contiguous nucleotide units comprised in the oligonucleotide.
    • 124. The method of embodiment 123, further comprising reacting the contiguous nucleotide sequence with a non-nucleotide conjugation moiety.
    • 125. A method for manufacturing the composition of embodiment 122, comprising mixing the oligonucleotide with a pharmaceutically acceptable diluent, carrier, salt and/or adjuvant.
    • 126. An in vivo or in vitro method for inducing UBE3A expression in a target cell where expression of paternal UBE3A is suppressed, said method comprising administering an oligonucleotide of any one of embodiments 1-112 or a conjugate of embodiment 113-121 or the pharmaceutical composition of embodiment 122 in an effective amount to said cell.
    • 127. The method of embodiment 126, wherein the expression of UBE3A is increased by at least 40% compared to a control.
    • 128. The method of embodiment 126 or 127, wherein the level of the SNHG14 transcript downstream of SNORD109B is reduced by at least 30% compared to a control.
    • 129. The method of embodiment 126-128, wherein the target cell is a neuronal cell.
    • 130. The method of embodiment 126-129, wherein the expression of SNORD115 is not significantly affected compared to a control.
    • 131. A method for treating or preventing a disease comprising administering a therapeutically or prophylactically effective amount of an oligonucleotide of embodiment 1-112 or a conjugate of embodiment 113-121 or the pharmaceutical composition of embodiment 122 to a subject suffering from or susceptible to the disease.
    • 132. The oligonucleotide of embodiment 1-112 or a conjugate of embodiment 113-121 or the pharmaceutical composition of embodiment 122, for use as a medicament for treatment or prevention of a disease in a subject.
    • 133. Use of the oligonucleotide of oligonucleotide of embodiment 1-112 or a conjugate of embodiment 113-121 for the preparation of a medicament for treatment or prevention of a disease in a subject.
    • 134. The method, the oligonucleotide or the use of embodiments 131-133, wherein the disease is associated with in vivo activity of UBE3A.
    • 135. The method, the oligonucleotide or the use of embodiments 131-134, wherein the disease is associated with reduced expression of UBE3A and/or reduced activity of UBE3A in neuronal cells.
    • 136. The method, the oligonucleotide or the use of embodiment 135, wherein the reduced expression of UBE3A and/or reduced activity of UBE3A is due to mutations in the maternal allele of the UBE3A gene.
    • 137. The method, the oligonucleotide or the use of embodiments 134-136, wherein the UBE3A expression is increased by at least 30%, or at least 50%, or at least 70%, or at least 90%, or at least 100%, or at least 150% or at least 200%, compared to the expression without the oligonucleotide of embodiment 1-112 or a conjugate of embodiment 113-121 or the pharmaceutical composition of embodiment 122.
    • 138. The method, the oligonucleotide or the use of embodiments 131-137, wherein the disease is Angelman syndrome.
    • 139. The method, the oligonucleotide or the use of embodiments 131-138, wherein the subject is a mammal.
    • 140. The method, the oligonucleotide or the use of embodiment 139, wherein the mammal is human.
    • 141. The method, the oligonucleotide or the use of embodiment 139 or 140, wherein the subject is an infant or a juvenile.

EXAMPLES Materials and Methods

TABLE_3 List of oligonucleotides or contiguous nucleobase sequences complementary to SEQ ID NO: 1 (motif sequences indicated by SEQ ID NO), oligonucleotide designs made from these, as well as specific oligonucleotide compounds (indicated by CMP ID NO) designed based on the motif sequence. Seq Start ID CMP SEQ_ID NO Mctif Design Compound ID_NO ΔG° NO 4 AACTTCATCAATATTTCCC 3-13-3 AACttcatcaatatttCCC 4_1 -23.36 1677 4 AACTTCATCAATATTTCCC 2-15-2 AActtcatcaatatttcCC 4_2 -19.60 1677 5 ACTTCATCAATATTTCCC 3-12-3 ACTtcatcaatatttCCC 5_1 -23.80 1677 5 ACTTCATCAATATTTCCC 2-14-2 ACttcatcaatatttcCC 5_2 -20.24 1677 6 CAACTTCATCAATATTTCCC 2-14-4 CAacttcatcaatattTCCC 6_1 -25.64 1677 6 CAACTTCATCAATATTTCCC 2-16-2 CAacttcatcaatatttcCC 6_2 -22.28 1677 7 CAACTTCATCAATATTTCC 4-13-2 CAACttcatcaatatttCC 7_1 -21.47 1678 7 CAACTTCATCAATATTTCC 2-15-2 CAacttcatcaatatttCC 7_2 -19.46 1678 8 CCAACTTCATCAATATTTCC 3-14-3 CCAacttcatcaatattTCC 8_1 -25.64 1678 9 CCCAACTTCATCAATATTTC 4-14-2 CCCAacttcatcaatattTC 9_1 -25.64 1679 10 ACCCAACTTCATCAATATTT 2-16-2 ACccaacttcatcaatatTT 10_1 -20.05 1680 11 CCCAACTTCATCAATATTT 4-13-2 CCCAacttcatcaatatTT 11_1 -23.96 1680 11 CCCAACTTCATCAATATTT 2-15-2 CCcaacttcatcaatatTT 11_2 -20.28 1680 12 ACCCAACTTCATCAATATT 4-13-2 ACCCaacttcatcaataTT 12_1 -23.64 1681 12 ACCCAACTTCATCAATATT 2-15-2 ACccaacttcatcaataTT 12_2 -19.18 1681 13 CCCAACTTCATCAATATT 4-12-2 CCCAacttcatcaataTT 13_1 -23.09 1681 13 CCCAACTTCATCAATATT 2-14-2 CCcaacttcatcaataTT 13_2 -19.41 1681 14 TACCCAACTTCATCAATAT 2-15-2 TAcccaacttcatcaatAT 14_1 -19.31 1682 15 TACCCAACTTCATCAATA 2-14-2 TAcccaacttcatcaaTA 15_1 -19.14 1683 16 TTACCCAACTTCATCAATA 2-15-2 TTacccaacttcatcaaTA 16_1 -19.74 1683 17 TTTACCCAACTTCATCAAT 4-13-2 TTTAcccaacttcatcaAT 17_1 -21.68 1684 17 TTTACCCAACTTCATCAAT 2-15-2 TTtacccaacttcatcaAT 17_2 -19.22 1684 18 ATACTTTACCCAACTTCAT 3-13-3 ATActttacccaacttCAT 18_1 -23.44 1688 18 ATACTTTACCCAACTTCAT 2-15-2 ATactttacccaacttcAT 18_2 -20.13 1688 19 TACTTTACCCAACTTCAT 3-12-3 TACtttacccaacttCAT 19_1 -22.78 1688 19 TACTTTACCCAACTTCAT 2-14-2 TActttacccaacttcAT 19_2 -19.30 1688 20 TTATACTTTACCCAACTTCA 2-16-2 TTatactttacccaacttCA 20_1 -21.40 1689 21 TCACTGTTCTGACTTT 3-10-3 TCActgttctgacTTT 21_1 -19.11 1712 22 TTCAATCTCTATCTCATCAT 2-16-2 TTcaatctctatctcatcAT 22_1 -19.42 4169 23 CTTCAATCTCTATCTCATCA 4-14-2 CTTCaatctctatctcatCA 23_1 -24.21 4170 23 CTTCAATCTCTATCTCATCA 2-16-2 CTtcaatctctatctcatCA 23_2 -22.04 4170 24 TTCAATCTCTATCTCATCA 2-15-2 TTcaatctctatctcatCA 24_1 -19.44 4170 25 CTTCAATCTCTATCTCATC 2-15-2 CTtcaatctctatctcaTC 25_1 -19.87 4171 26 ACTTCAATCTCTATCTCAT 3-13-3 ACTtcaatctctatctCAT 26_1 -22.36 4172 26 ACTTCAATCTCTATCTCAT 2-15-2 ACttcaatctctatctcAT 26_2 -19.08 4172 27 CACTTCAATCTCTATCTCAT 2-16-2 CActtcaatctctatctcAT 27_1 -20.98 4172 28 ACTTCAATCTCTATCTCA 2-12-4 ACttcaatctctatCTCA 28_1 -21.96 4173 28 ACTTCAATCTCTATCTCA 2-14-2 ACttcaatctctatctCA 28_2 -19.10 4173 29 CACTTCAATCTCTATCTCA 2-13-4 CActtcaatctctatCTCA 29_1 -23.86 4173 29 CACTTCAATCTCTATCTCA 2-15-2 CActtcaatctctatctCA 29_2 -21.00 4173 30 ACACTTCAATCTCTATCTC 2-15-2 ACacttcaatctctatcTC 30_1 -19.38 4174 31 TACACTTCAATCTCTATCTC 2-14-4 TAcacttcaatctctaTCTC 31_1 -23.31 4174 31 TACACTTCAATCTCTATCTC 2-16-2 TAcacttcaatctctatcTC 31_2 -20.53 4174 32 TACACTTCAATCTCTATCT 4-13-2 TACActtcaatctctatCT 32_1 -22.34 4175 33 CTTTGTCTCTCTTTACT 2-13-2 CTttgtctctctttaCT 33_1 -19.36 4374 34 TATACCTTTCTTTAACCC 3-12-3 TATacctttctttaaCCC 34_1 -24.89 8118 34 TATACCTTTCTTTAACCC 2-14-2 TAtacctttctttaacCC 34_2 -20.83 8118 34 TATACCTTTCTTTAACCC 1-3-1- TataCctttcttTaAcCC 34_3 -21.63 8116 7-1-1- 1-1-2 34 TATACCTTTCTTTAACCC 1-4-1- TatacCtttcttTaacCC 34_4 -21.31 8116 6-1-3-2 34 TATACCTTTCTTTAACCC 1-2-1- TatAcCtttctttAAcCC 34_5 -21.51 8116 1-1-7- 2-1-2 34 TATACCTTTCTTTAACCC 2-3-1- TAtacCtttctttAacCC 34_6 -21.84 8116 7-1-2-2 34 TATACCTTTCTTTAACCC 2-13-3 TAtacctttctttaaCCC 34_7 -23.21 8116 35 TGTTTATACCCTTTCC 2-12-2 TGtttataccctttCC 35_1 -20.33 9212 35 TGTTTATACCCTTTCC 4-10-2 TGTTtataccctttCC 35_2 -22.69 9212 36 TCTCCTTTATGACTCC 2-10-4 TCtcctttatgaCTCC 36_1 -23.29 10839 37 CTTCTCCTTTATGACTC 2-13-2 CTtctcctttatgacTC 37_1 -19.26 10840 38 CCATTTATTTCCATTTATT 4-13-2 CCATttatttccatttaTT 38_1 -22.32 15567 38 CCATTTATTTCCATTTATT 2-15-2 CCatttatttccatttaTT 38_2 -19.61 15567 38 CCATTTATTTCCATTTATT 1-2-1- CcaTttatttccaTTtATT 38_3 -20.02 15567 9-2-1-3 38 CCATTTATTTCCATTTATT 1-1-1- CcAtTtatttccaTtTaTT 38_4 -18.95 15567 1-1-8- 1-1-1- 1-2 38 CCATTTATTTCCATTTATT 2-2-1- CCatTtatttcca_TttaTT 38_5 -20.35 15567 8-1-3-2 38 CCATTTATTTCCATTTATT 1-2-3- CcaTTTatttccAtttATT 38_6 -20.87 15567 6-1-3-3 39 CTTTCCATTTATTTCCATTT 2-14-4 CTttccatttatttccATTT 39_1 -23.14 15570 39 CTTTCCATTTATTTCCATTT 1-13- CtttccatttatttCcAtTT 39_2 -20.96 15570 1-1-1- 1-2 39 CTTTCCATTTATTTCCATTT 1-13- CtttccatttatttCcatTT 39_3 -20.91 15570 1-3-2 39 CTTTCCATTTATTTCCATTT 1-3-1- CtttCcAtttatttccatTT 39_4 -20.96 15570 1-1-11- 2 39 CTTTCCATTTATTTCCATTT 1-1-1- CtTtccAtttatttccAtTT 39_5 -20.54 15570 3-1-9- 1-1-2 40 TCTTTCCATTTATTTCCATT 2-14-4 TCtttccatttatttcCATT 40_1 -24.62 15571 40 TCTTTCCATTTATTTCCATT 2-13- TCtttccatttatttCcATT 40_2 -23.39 15571 1-1-3 40 TCTTTCCATTTATTTCCATT 2-13- TCtttccatttatttCcaTT 40_3 -22.53 15571 1-2-2 40 TCTTTCCATTTATTTCCATT 2-14- TCtttccatttatttcCaTT 40_4 -22.34 15571 1-1-2 40 TCTTTCCATTTATTTCCATT 2-3-1- TCtttCcatttatttccATT 40_5 -23.39 15571 11-3 40 TCTTTCCATTTATTTCCATT 2-4-1- TCtttcCatttatttccATT 40_6 -23.20 15571 10-3 40 TCTTTCCATTTATTTCCATT 2-3-1- TCtttCcatttatttccaTT 40_7 -22.53 15571 12-2 40 TCTTTCCATTTATTTCCATT 2-4-1- TCtttcCatttatttccaTT 40_8 -22.34 15571 11-2 41 ATTACCCATCCGTTCT 2-12-2 ATtacccatccgttCT 41_1 -21.15 21965 42 GCATTAGGCACATTACAT 3-12-3 GCAttaggcacattaCAT 42_1 -23.96 22211 43 ATTATTATTTAACCTTCCTA 2-16-2 ATtattatttaaccttccTA 43_1 -19.28 30451 44 ACATTATTATTTAACCTTCC 4-14-2 ACATtattatttaaccttCC 44_1 -22.84 30453 44 ACATTATTATTTAACCTTCC 2-16-2 ACattattatttaaccttCC 44_2 -20.13 30453 45 CATTATTATTTAACCTTCC 4-13-2 CATTattatttaaccttCC 45_1 -22.04 30453 45 CATTATTATTTAACCTTCC 2-15-2 CAttattatttaaccttCC 45_2 -19.55 30453 46 CCTCTGCTTATAACTTT 2-13-2 CCtctgcttataactTT 46_1 -19.15 30699 47 CTACTATACTTTCCTCT 2-11-4 CTactatactttcCTCT 47_1 -22.32 30711 48 GTTCTACTATACTTTCC 4-11-2 GTTCtactatactttCC 48_1 -21.69 30714 48 GTTCTACTATACTTTCC 2-13-2 GTtctactatactttCC 48_2 -19.21 30714 48 GTTCTACTATACTTTCC 1-2-1- GttCtactataCTttCC 48_3 -20.83 30712 7-2-2-2 48 GTTCTACTATACTTTCC 2-9-1- GTtctactataCtttCC 48_4 -20.20 30712 3-2 48 GTTCTACTATACTTTCC 1-2-1- GttCtactatactTtCC 48_5 -18.95 30712 9-1-1-2 48 GTTCTACTATACTTTCC 2-1-1- GTtCtactatacttTCC 48_6 -21.18 30712 10-3 48 GTTCTACTATACTTTCC 1-3-1- GttcTactatactttCC 48_7 -18.61 30712 10-2 49 CACCTGATAACAGACCCT 3-12-3 CACctgataacagacCCT 49_1 -26.38 36068 50 CACCTGATAACAGACC 3-10-3 CACctgataacagACC 50_1 -21.10 36070 51 CCCACCAAAGGATATATT 3-12-3 CCCaccaaaggatatATT 51_1 -23.47 37208 52 ACCAGCTACAGGAACCTC 3-12-3 ACCagctacaggaacCTC 52_1 -26.57 46132 53 CTATATCTCACTCCTATTT 4-13-2 CTATatctcactcctatTT 53_1 -23.07 48143 53 CTATATCTCACTCCTATTT 2-13-4 CTatatctcactcctATTT 53_2 -22.12 48143 54 CTATATCTCACTCCTATT 2-14-2 CTatatctcactcctaTT 54_1 -19.40 48144 54 CTATATCTCACTCCTATT 2-12-4 CTatatctcactccTATT 54_2 -22.28 48144 54 CTATATCTCACTCCTATT 3-12-3 CTAtatctcactcctATT 54_3 -21.44 48144 55 CTACTATATCTCACTCCTAT 2-16-2 CTactatatctcactcctAT 55_1 -22.00 48145 55 CTACTATATCTCACTCCTAT 2-14-4 CTactatatctcactcCTAT 55_2 -25.54 48145 56 TACTATATCTCACTCCTAT 2-13-4 TActatatctcactcCTAT 56_1 -23.29 48145 57 CTACTATATCTCACTCCTA 2-15-2 CTactatatctcactccTA 57_1 -21.91 48146 58 TACTATATCTCACTCCTA 2-14-2 TActatatctcactccTA 58_1 -19.66 48146 58 TACTATATCTCACTCCTA 2-12-4 TActatatctcactCCTA 58_2 -23.59 48146 58 TACTATATCTCACTCCTA 3-12-3 TACtatatctcactcCTA 58_3 -22.62 48146 59 CTACTATATCTCACTCCT 2-14-2 CTactatatctcactcCT 59_1 -21.25 48147 59 CTACTATATCTCACTCCT 4-12-2 CTACtatatctcactcCT 59_2 -23.87 48147 60 CTACTATATCTCACTCC 2-13-2 CTactatatctcactCC 60_1 -20.13 48148 60 CTACTATATCTCACTCC 2-11-4 CTactatatctcaCTCC 60_2 -23.00 48148 60 CTACTATATCTCACTCC 3-11-3 CTActatatctcacTCC 60_3 -22.56 48148 61 CCTACTATATCTCACTC 2-11-4 CCtactatatctcACTC 61_1 -21.93 48149 62 CTCCTACTATATCTCACTC 4-13-2 CTCCtactatatctcacTC 62_1 -25.69 48149 63 TCCTACTATATCTCACTC 3-12-3 TCCtactatatctcaCTC 63_1 -23.88 48149 64 CTCCTACTATATCTCACT 4-12-2 CTCCtactatatctcaCT 64_1 -24.87 48150 64 CTCCTACTATATCTCACT 3-12-3 CTCctactatatctcACT 64_2 -22.93 48150 65 TTTCCTCTCCTACTATATC 2-15-2 TTtcctctcctactataTC 65_1 -21.23 48155 66 ATCCATATCCTTTCCT 3-10-3 ATCcatatcctttCCT 66_1 -24.02 48168 67 CATCCATATCCTTTCCT 4-11-2 CATCcatatcctttcCT 67_1 -24.94 48168 68 ATCATCCATATCCTTTCC 4-12-2 ATCAtccatatcctttCC 68_1 -25.69 48169 69 CATCATCCATATCCTTTC 4-12-2 CATCatccatatccttTC 69_1 -23.32 48170 69 CATCATCCATATCCTTTC 2-14-2 CAtcatccatatccttTC 69_2 -20.72 48170 69 CATCATCCATATCCTTTC 2-12-4 CAtcatccatatccTTTC 69_3 -22.56 48170 70 TACATCATCCATATCCTTTC 2-16-2 TAcatcatccatatccttTC 70_1 -22.45 48170 70 TACATCATCCATATCCTTTC 4-14-2 TACAtcatccatatccttTC 70_2 -25.00 48170 70 TACATCATCCATATCCTTTC 2-14-4 TAcatcatccatatccTTTC 70_3 -24.29 48170 71 ACATCATCCATATCCTTT 3-12-3 ACAtcatccatatccTTT 71_1 -22.11 48171 72 CATCATCCATATCCTTT 2-13-2 CAtcatccatatcctTT 72_1 -19.04 48171 72 CATCATCCATATCCTTT 4-11-2 CATCatccatatcctTT 72_2 -21.64 48171 73 TACATCATCCATATCCTTT 2-15-2 TAcatcatccatatcctTT 73_1 -20.76 48171 73 TACATCATCCATATCCTTT 2-13-4 TAcatcatccatatcCTTT 73_2 -23.36 48171 73 TACATCATCCATATCCTTT 3-13-3 TACatcatccatatccTTT 73_3 -22.88 48171 74 ATACATCATCCATATCCTT 2-15-2 ATacatcatccatatccTT 74_1 -20.80 48172 74 ATACATCATCCATATCCTT 4-13-2 ATACatcatccatatccTT 74_2 -23.12 48172 75 TACATCATCCATATCCTT 2-14-2 TAcatcatccatatccTT 75_1 -19.97 48172 75 TACATCATCCATATCCTT 4-12-2 TACAtcatccatatccTT 75_2 -22.52 48172 76 TATACATCATCCATATCCTT 2-16-2 TAtacatcatccatatccTT 76_1 -21.36 48172 77 ATACATCATCCATATCCT 3-12-3 ATAcatcatccatatCCT 77_1 -24.15 48173 77 ATACATCATCCATATCCT 2-14-2 ATacatcatccatatcCT 77_2 -20.55 48173 77 ATACATCATCCATATCCT 2-13-3 ATacatcatccatatCCT 77_3 -22.92 48173 78 ATATACATCATCCATATCCT 2-16-2 ATatacatcatccatatcCT 78_1 -22.04 48173 79 TACATCATCCATATCCT 2-11-4 TAcatcatccataTCCT 79_1 -23.21 48173 79 TACATCATCCATATCCT 2-13-2 TAcatcatccatatcCT 79_2 -19.71 48173 79 TACATCATCCATATCCT 4-11-2 TACAtcatccatatcCT 79_3 -22.27 48173 80 TATACATCATCCATATCCT 2-15-2 TAtacatcatccatatcCT 80_1 -21.11 48173 80 TATACATCATCCATATCCT 3-13-3 TATacatcatccatatCCT 80_2 -25.15 48173 80 TATACATCATCCATATCCT 4-13-2 TATAcatcatccatatcCT 80_3 -24.01 48173 81 ATACATCATCCATATCC 3-11-3 ATAcatcatccataTCC 81_1 -21.79 48174 82 ATATACATCATCCATATCC 4-13-2 ATATacatcatccatatCC 82_1 -23.73 48174 82 ATATACATCATCCATATCC 2-15-2 ATatacatcatccatatCC 82_2 -20.93 48174 83 TATACATCATCCATATCC 2-14-2 TAtacatcatccatatCC 83_1 -20.00 48174 83 TATACATCATCCATATCC 4-12-2 TATAcatcatccatatCC 83_2 -22.90 48174 84 TATATACATCATCCATATCC 2-16-2 TAtatacatcatccatatCC 84_1 -21.49 48174 84 TATATACATCATCCATATCC 4-14-2 TATAtacatcatccatatCC 84_2 -24.29 48174 85 GCTTCATATTTCTCCA 2-12-2 GCttcatatttctcCA 85_1 -20.44 49345 85 GCTTCATATTTCTCCA 2-11-3 GCttcatatttctCCA 85_2 -22.81 49345 86 CATCTTGTTCTTTACCT 2-13-2 CAtcttgttctttacCT 86_1 -19.67 49581 87 TATATTCACCATTGCC 2-10-4 TAtattcaccatTGCC 87_1 -22.70 49724 88 CCTTATATTCACCATTG 2-13-2 CCttatattcaccatTG 88_1 -19.44 49726 88 CCTTATATTCACCATTG 2-11-4 CCttatattcaccATTG 88_2 -21.25 49726 89 CCTCCTTATATTCACC 4-10-2 CCTCcttatattcaCC 89_1 -24.64 49730 90 CCCTTCCTTTATTCAA 3-10-3 CCCttcctttattCAA 90_1 -23.86 50189 91 CCTTACTGTTAAATCCT 2-13-2 CCttactgttaaatcCT 91_1 -19.81 50475 92 CAGGCAGATAACCTCCAA 3-12-3 CAGgcagataacctcCAA 92_1 -25.31 52419 93 CAGCAGGCAGATAACCTC 3-12-3 CAGcaggcagataacCTC 93_1 -25.88 52422 94 CGAATCTTGACATACAGG 3-12-3 CGAatcttgacatacAGG 94_1 -21.47 53955 95 CTCATACTTGCTTTAAT 4-11-2 CTCAtacttgctttaAT 95_1 -19.10 60821 95 CTCATACTTGCTTTAAT 2-13-2 CTcatacttgctttaAT 95_2 -16.35 60821 96 ACATCTCATACTTGCTT 2-11-4 ACatctcatacttGCTT 96_1 -21.31 60825 96 ACATCTCATACTTGCTT 2-13-2 ACatctcatacttgcTT 96_2 -17.66 60825 96 ACATCTCATACTTGCTT 2-12-3 ACatctcatacttgCTT 96_3 -19.52 60825 97 ACATCTCATACTTGCT 2-10-4 ACatctcatactTGCT 97_1 -21.18 60826 97 ACATCTCATACTTGCT 2-12-2 ACatctcatacttgCT 97_2 -17.70 60826 97 ACATCTCATACTTGCT 2-11-3 ACatctcatacttGCT 97_3 -19.49 60826 97 ACATCTCATACTTGCT 4-10-2 ACATctcatacttgCT 97_4 -20.48 60826 98 TACATCTCATACTTGCT 2-11-4 TAcatctcatactTGCT 98_1 -22.33 60826 98 TACATCTCATACTTGCT 2-13-2 TAcatctcatacttgCT 98_2 -18.85 60826 98 TACATCTCATACTTGCT 4-11-2 TACAtctcatacttgCT 98_3 -21.40 60826 99 CCTACATCTCATACTTGC 3-12-3 CCTacatctcatactTGC 99_1 -26.29 60827 99 CCTACATCTCATACTTGC 2-14-2 CCtacatctcatacttGC 99_2 -22.98 60827 99 CCTACATCTCATACTTGC 2-13-3 CCtacatctcatactTGC 99_3 -24.67 60827 99 CCTACATCTCATACTTGC 2-12-4 CCtacatctcatacTTGC 99_4 -25.70 60827 100 CTACATCTCATACTTGC 3-11-3 CTAcatctcatactTGC 100_1 -22.33 60827 100 CTACATCTCATACTTGC 2-13-2 CTacatctcatacttGC 100_2 -19.41 60827 100 CTACATCTCATACTTGC 2-12-3 CTacatctcatactTGC 100_3 -21.10 60827 101 TACATCTCATACTTGC 3-10-3 TACatctcatactTGC 101_1 -19.94 60827 101 TACATCTCATACTTGC 2-12-2 TAcatctcatacttGC 101_2 -17.15 60827 101 TACATCTCATACTTGC 2-11-3 TAcatctcatactTGC 101_3 -18.85 60827 101 TACATCTCATACTTGC 4-10-2 TACAtctcatacttGC 101_4 -19.71 60827 102 CCTACATCTCATACTTG 4-11-2 CCTAcatctcatactTG 102_1 -22.52 60828 102 CCTACATCTCATACTTG 2-13-2 CCtacatctcatactTG 102_2 -19.67 60828 102 CCTACATCTCATACTTG 3-12-2 CCTacatctcatactTG 102_3 -21.29 60828 102 CCTACATCTCATACTTG 3-11-3 CCTacatctcatacTTG 102_4 -22.31 60828 103 ACCTACATCTCATACTT 3-11-3 ACCtacatctcataCTT 103_1 -21.93 60829 103 ACCTACATCTCATACTT 2-13-2 ACctacatctcatacTT 103_2 -17.76 60829 103 ACCTACATCTCATACTT 2-11-4 ACctacatctcatACTT 103_3 -20.03 60829 103 ACCTACATCTCATACTT 3-12-2 ACCtacatctcatacTT 103_4 -20.26 60829 104 CCTACATCTCATACTT 3-10-3 CCTacatctcataCTT 104_1 -21.50 60829 104 CCTACATCTCATACTT 2-12-2 CCtacatctcatacTT 104_2 -18.21 60829 104 CCTACATCTCATACTT 2-10-4 CCtacatctcatACTT 104_3 -20.48 60829 105 TACCTACATCTCATACTT 4-12-2 TACCtacatctcatacTT 105_1 -22.49 60829 105 TACCTACATCTCATACTT 2-14-2 TAcctacatctcatacTT 105_2 -18.81 60829 105 TACCTACATCTCATACTT 2-13-3 TAcctacatctcataCTT 105_3 -20.48 60829 105 TACCTACATCTCATACTT 2-12-4 TAcctacatctcatACTT 105_4 -21.08 60829 106 TTACCTACATCTCATACTT 3-13-3 TTAcctacatctcataCTT 106_1 -22.30 60829 106 TTACCTACATCTCATACTT 2-15-2 TTacctacatctcatacTT 106_2 -19.40 60829 106 TTACCTACATCTCATACTT 2-14-3 TTacctacatctcataCTT 106_3 -21.08 60829 106 TTACCTACATCTCATACTT 2-13-4 TTacctacatctcatACTT 106_4 -21.67 60829 107 ACCTACATCTCATACT 4-10-2 ACCTacatctcataCT 107_1 -21.72 60830 107 ACCTACATCTCATACT 2-12-2 ACctacatctcataCT 107_2 -17.61 60830 107 ACCTACATCTCATACT 3-11-2 ACCtacatctcataCT 107_3 -20.10 60830 107 ACCTACATCTCATACT 2-10-4 ACctacatctcaTACT 107_4 -20.11 60830 108 TACCTACATCTCATACT 4-11-2 TACCtacatctcataCT 108_1 -22.34 60830 108 TACCTACATCTCATACT 2-13-2 TAcctacatctcataCT 108_2 -18.66 60830 108 TACCTACATCTCATACT 3-12-2 TACctacatctcataCT 108_3 -19.85 60830 108 TACCTACATCTCATACT 3-11-3 TACctacatctcatACT 108_4 -20.44 60830 109 TTACCTACATCTCATACT 2-12-4 TTacctacatctcaTACT 109_1 -21.75 60830 109 TTACCTACATCTCATACT 2-14-2 TTacctacatctcataCT 109_2 -19.25 60830 109 TTACCTACATCTCATACT 3-13-2 TTAcctacatctcataCT 109_3 -20.48 60830 109 TTACCTACATCTCATACT 3-12-3 TTAcctacatctcatACT 109_4 -21.08 60830 110 TTACCTACATCTCATAC 3-11-3 TTAcctacatctcaTAC 110_1 -19.50 60831 110 TTACCTACATCTCATAC 2-13-2 TTacctacatctcatAC 110_2 -16.37 60831 111 GTTACCTACATCTCATA 2-11-4 GTtacctacatctCATA 111_1 -21.69 60832 111 GTTACCTACATCTCATA 2-13-2 GTtacctacatctcaTA 111_2 -18.74 60832 111 GTTACCTACATCTCATA 3-12-2 GTTacctacatctcaTA 111_3 -19.98 60832 112 GTTACCTACATCTCAT 3-10-3 GTTacctacatctCAT 112_1 -20.69 60833 112 GTTACCTACATCTCAT 2-12-2 GTtacctacatctcAT 112_2 -17.37 60833 113 ATATACCCAAAGGCACCT 3-12-3 ATAtacccaaaggcaCCT 113_1 -25.99 62200 114 TCTACTCATCCTTTAACTCA 2-14-4 TCtactcatcctttaaCTCA 114_1 -25.63 62251 115 CCTTAATCTGTATCACT 2-13-2 CCttaatctgtatcaCT 115_1 -19.58 62286 116 CCATACACAGCACATA 2-12-2 CCatacacagcacaTA 116_1 -19.04 62424 117 CTCCATACACAGCACAT 2-13-2 CTccatacacagcacAT 117_1 -20.08 62425 118 CAGAATAATTCTCCTCC 2-13-2 CAgaataattctcctCC 118_1 -19.86 62441 119 GTCCTACATATATACC 4-10-2 GTCCtacatatataCC 119_1 -22.09 66380 120 TGCTTCCTTACTAACC 4-10-2 TGCTtccttactaaCC 120_1 -23.93 66701 120 TGCTTCCTTACTAACC 2-12-2 TGcttccttactaaCC 120_2 -20.10 66701 121 CCCTTTGTAATCATCT 4-10-2 CCCTttgtaatcatCT 121_1 -23.44 66838 122 TCCCTTTGTAATCATCT 2-13-2 TCcctttgtaatcatCT 122_1 -19.97 66838 123 CTGCCATCAATACCAT 2-12-2 CTgccatcaataccAT 123_1 -19.14 68918 124 TCACTGCCATCAATACC 2-13-2 TCactgccatcaataCC 124_1 -21.35 68920 125 ATTCTTACTTTATTCCTCA 2-15-2 ATtcttactttattcctCA 125_1 -20.16 70033 126 TCACTTTCCAGATATCA 4-11-2 TCACtttccagatatCA 126_1 -21.61 77567 126 TCACTTTCCAGATATCA 2-13-2 TCactttccagatatCA 126_2 -18.65 77567 127 TCCTTCAAATTCCACATAC 3-13-3 TCCttcaaattccacaTAC 127_1 -24.09 82053 128 ACATGTCCCTTTATATT 4-11-2 ACATgtccctttataTT 128_1 -20.87 92323 128 ACATGTCCCTTTATATT 2-13-2 ACatgtccctttataTT 128_2 -17.66 92323 128 ACATGTCCCTTTATATT 3-12-2 ACAtgtccctttataTT 128_3 -19.13 92323 128 ACATGTCCCTTTATATT 3-11-3 ACAtgtccctttatATT 128_4 -20.03 92323 129 ACATGTCCCTTTATAT 3-10-3 ACAtgtccctttaTAT 129_1 -20.11 92324 129 ACATGTCCCTTTATAT 2-12-2 ACatgtccctttatAT 129_2 -16.74 92324 130 CCAAGAAAGGAGCAAGCT 3-12-3 CCAagaaaggagcaaGCT 130_1 -25.26 97146 131 TCCAAGAAAGGAGCAAGC 3-12-3 TCCaagaaaggagcaAGC 131_1 -24.12 97147 132 CTCATCCCTCCAAGAAA 4-11-2 CTCAtccctccaagaAA 132_1 -22.58 97156 132 CTCATCCCTCCAAGAAA 2-13-2 CTcatccctccaagaAA 132_2 -19.83 97156 132 CTCATCCCTCCAAGAAA 3-12-2 CTCatccctccaagaAA 132_3 -21.11 97156 133 TCATCCCTCCAAGAAA 4-10-2 TCATccctccaagaAA 133_1 -20.41 97156 133 TCATCCCTCCAAGAAA 2-12-2 TCatccctccaagaAA 133_2 -17.63 97156 133 TCATCCCTCCAAGAAA 3-11-2 TCAtccctccaagaAA 133_3 -19.09 97156 133 TCATCCCTCCAAGAAA 3-10-3 TCAtccctccaagAAA 133_4 -19.81 97156 134 CACCTCCCTATTACATAAA 4-13-2 CACCtccctattacataAA 134_1 -24.18 100018 134 CACCTCCCTATTACATAAA 2-15-2 CAcctccctattacataAA 134_2 -20.51 100018 135 CACCTCCCTATTACATAA 4-12-2 CACCtccctattacatAA 135_1 -23.75 100019 135 CACCTCCCTATTACATAA 2-14-2 CAcctccctattacatAA 135_2 -20.07 100019 136 CCTCCCTATTACATAA 2-12-2 CCtccctattacatAA 136_1 -18.40 100019 137 CTAAATCTTCCAATTCATA 2-15-2 CTaaatcttccaattcaTA 137_1 -18.12 106139 138 TATCCCTTGATTATCCT 2-13-2 TAtcccttgattatcCT 138_1 -20.68 109406 139 CCTCTTTGTCAAATACT 2-13-2 CCtctttgtcaaataCT 139_1 -19.30 110768 140 CAGCTTATTTACCTCTT 2-13-2 CAgcttatttacctcTT 140_1 -19.30 114828 141 ACTCTTTACCTCTAACACT 4-13-2 ACTCtttacctctaacaCT 141_1 -24.26 117468 142 TTACTCTTTACCTCTAACAC 3-14-3 TTActctttacctctaaCAC 142_1 -23.23 117469 143 CCAACCTAATACCTTAATA 2-15-2 CCaacctaataccttaaTA 143_1 -20.27 118639 144 TACCAACCTAATACCTTAA 2-15-2 TAccaacctaataccttAA 144_1 -18.32 118641 145 CCAATACCCACAAACC 3-10-3 CCAatacccacaaACC 145_1 -23.17 124162 145 CCAATACCCACAAACC 2-12-2 CCaatacccacaaaCC 145_2 -20.85 124162 146 CCATTATTCTACTTTGT 3-11-3 CCAttattctacttTGT 146_1 -21.79 125501 146 CCATTATTCTACTTTGT 2-13-2 CCattattctactttGT 146_2 -18.63 125501 147 CATTTCCTTATCTTCACA 2-14-2 CAtttccttatcttcaCA 147_1 -20.39 125529 148 TCATTTCCTTATCTTCACA 4-13-2 TCATttccttatcttcaCA 148_1 -24.13 125529 149 AATAATTCCTCATTTCCT 2-14-2 AAtaattcctcatttcCT 149_1 -18.01 125539 150 ACAATAATTCCTCATTTCC 3-13-3 ACAataattcctcattTCC 150_1 -22.71 125540 150 ACAATAATTCCTCATTTCC 2-15-2 ACaataattcctcatttCC 150_2 -20.23 125540 151 TATTGAACCAATTCTA 3-10-3 TATtgaaccaattCTA 151_1 -16.93 4806 152 CATATTGAACCAATTC 4-10-2 CATAttgaaccaatTC 152_1 -16.32 4808 153 TCATATTGAACCAATT 4-10-2 TCATattgaaccaaTT 153_1 -16.14 4809 154 CATCATATTGAACCAA 2-10-4 CAtcatattgaaCCAA 154_1 -17.65 4811 155 TCATCATATTGAACCA 3-10-3 TCAtcatattgaaCCA 155_1 -19.40 4812 156 CACAATCAACAACAAATA 4-12-2 CACAatcaacaacaaaTA 156_1 -16.16 4972 157 TACACAATCAACAACAAAT 4-13-2 TACAcaatcaacaacaaAT 157_1 -16.76 4973 158 CTGTACACAATCAACA 4-10-2 CTGTacacaatcaaCA 158_1 -19.05 4979 159 CACTAATAATTCACTTT 4-11-2 CACTaataattcactTT 159_1 -16.39 5058 160 CAACATTATTGACACT 2-10-4 CAacattattgaCACT 160_1 -17.17 5071 161 AAACTTTCCCAACATTAT 2-12-4 AAactttcccaacaTTAT 161_1 -18.69 5078 162 TCCTATATTCTCTTAAA 4-11-2 TCCTatattctcttaAA 162_1 -18.58 5094 163 TTTCCTATATTCTCTTA 4-11-2 TTTCctatattctctTA 163_1 -18.69 5096 164 CAAGTTTCCTATATTCT 4-11-2 CAAGtttcctatattCT 164_1 -19.97 5100 165 CAAGTTTCCTATATTC 4-10-2 CAAGtttcctatatTC 165_1 -17.47 5101 166 CATTCTATCTGCCAAA 2-10-4 CAttctatctgcCAAA 166_1 -18.36 5218 167 CCATTCTATCTGCCAAA 2-11-4 CCattctatctgcCAAA 167_1 -22.08 5218 168 TATAGCCATTCTATCT 4-10-2 TATAgccattctatCT 168_1 -20.63 5224 169 TTATAGCCATTCTATCT 4-11-2 TTATagccattctatCT 169_1 -20.82 5224 169 TTATAGCCATTCTATCT 1-10-3- TtatagccattCTAtCT 169_2 -20.51 5224 1-2 169 TTATAGCCATTCTATCT 2-9-1- TTatagccattCtaTCT 169_3 -20.12 5224 2-3 169 TTATAGCCATTCTATCT 1-1-1- TtAtagccattCTaTCT 169_4 -20.59 5224 8-2-1-3 169 TTATAGCCATTCTATCT 1-3-1- TtatAgccattCTatCT 169_5 -19.97 5224 6-2-2-2 169 TTATAGCCATTCTATCT 3-8-1- TTAtagccattCtatCT 169_6 -20.13 5224 3-2 169 TTATAGCCATTCTATCT 1-10-2- TtatagccattCTatCT 169_7 -19.37 5224 2-2 169 TTATAGCCATTCTATCT 2-9-1- TTatagccattCtATCT 169_8 -21.02 5224 1-4 169 TTATAGCCATTCTATCT 1-1-1- TtAtagccattCtATCT 169_9 -19.88 5224 8-1-1-4 169 TTATAGCCATTCTATCT 1-2-1- TtaTagccattCtATCT 169_10 -20.65 5224 7-1-1-4 169 TTATAGCCATTCTATCT 1-3-1- TtatAgccattCtATCT 169_11 -20.38 5224 6-1-1-4 169 TTATAGCCATTCTATCT 1-10- TtatagccattCtATCT 169_12 -19.78 5224 1-1-4 169 TTATAGCCATTCTATCT 3-8-1- TTAtagccattCtAtCT 169_13 -20.22 5224 1-1-1-2 169 TTATAGCCATTCTATCT 2-1-1- TTaTagccattCtAtCT 169_14 -19.96 5224 7-1-1- 1-1-2 169 TTATAGCCATTCTATCT 2-2-1- TTatAgccattCtAtCT 169_15 -19.69 5224 6-1-1- 1-1-2 169 TTATAGCCATTCTATCT 2-9-1- TTatagccattCtAtCT 169_16 -19.09 5224 1-1-1-2 169 TTATAGCCATTCTATCT 1-2-2- TtaTAgccattCtAtCT 169_17 -20.35 5224 6-1-1- 1-1-2 169 TTATAGCCATTCTATCT 1-2-1- TtaTagccattCtAtCT 169_18 -18.72 5224 7-1-1- 1-1-2 169 TTATAGCCATTCTATCT 1-3-1- TtatAgccattCtAtCT 169_19 -18.45 5224 6-1-1- 1-1-2 169 TTATAGCCATTCTATCT 2-2-1- TTatAgccattCtaTCT 169_20 -20.71 5224 6-1-2-3 169 TTATAGCCATTCTATCT 1-1-2- TtATagccattCtaTCT 169_21 -20.65 5224 7-1-2-3 169 TTATAGCCATTCTATCT 1-1-1- TtAtAgccattCtaTCT 169_22 -19.57 5224 1-1-6- 1-2-3 169 TTATAGCCATTCTATCT 1-1-1- TtAtagccattCtaTCT 169_23 -18.98 5224 8-1-2-3 169 TTATAGCCATTCTATCT 4-7-1- TTATagccattCtatCT 169_24 -21.80 5224 3-2 169 TTATAGCCATTCTATCT 3-1-1- TTAtAgccattCtatCT 169_25 -20.72 5224 6-1-3-2 169 TTATAGCCATTCTATCT 2-1-1- TTaTagccattCtatCT 169_26 -19.86 5224 7-1-3-2 169 TTATAGCCATTCTATCT 2-2-1- TTatAgccattCtatCT 169_27 -19.59 5224 6-1-3-2 169 TTATAGCCATTCTATCT 2-9-1- TTatagccattCtatCT 169_28 -18.99 5224 3-2 169 TTATAGCCATTCTATCT 1-1-3- TtATAgccattCtatCT 169_29 -21.16 5224 6-1-3-2 169 TTATAGCCATTCTATCT 1-1-2- TtATagccattCtatCT 169_30 -19.53 5224 7-1-3-2 169 TTATAGCCATTCTATCT 1-1-1- TtAtAgccattCtatCT 169_31 -18.45 5224 1-1-6- 1-3-2 169 TTATAGCCATTCTATCT 1-2-2- TtaTAgccattCtatCT 169_32 -20.25 5224 6-1-3-2 169 TTATAGCCATTCTATCT 1-2-1- TtaTagccattCtatCT 169_33 -18.62 5224 7-1-3-2 169 TTATAGCCATTCTATCT 1-3-1- TtatAgccattCtatCT 169_34 -18.35 5224 6-1-3-2 169 TTATAGCCATTCTATCT 1-1-1- TtAtagccattcTATCT 169_35 -20.88 5224 9-5 169 TTATAGCCATTCTATCT 2-10- TTatagccattcTAtCT 169_36 -20.09 5224 2-1-2 169 TTATAGCCATTCTATCT 1-1-1- TtAtagccattcTAtCT 169_37 -18.95 5224 9-2-1-2 169 TTATAGCCATTCTATCT 1-2-1- Tta_TagccattcTAtCT 169_38 -19.72 5224 8-2-1-2 169 TTATAGCCATTCTATCT 1-3-1- TtatAgccattcTAtCT 169_39 -19.44 5224 7-2-1-2 169 TTATAGCCATTCTATCT 1-11- TtatagccattcTAtCT 169_40 -18.85 5224 2-1-2 169 TTATAGCCATTCTATCT 3-9-1- TTAtagccattcTaTCT 169_41 -21.21 5224 1-3 169 TTATAGCCATTCTATCT 1-1-1- TtAtagccattcTaTCT 169_42 -18.94 5224 9-1-1-3 169 TTATAGCCATTCTATCT 3-9-1- TTAtagccattcTatCT 169_43 -20.09 5224 2-2 169 TTATAGCCATTCTATCT 1-2-1- TtaTagccattcTatCT 169_44 -18.58 5224 8-1-2-2 169 TTATAGCCATTCTATCT 1-3-1- TtatAgccattcTatCT 169_45 -18.31 5224 7-1-2-2 169 TTATAGCCATTCTATCT 1-1-1- TtAtagccattctATCT 169_46 -18.90 5224 10-4 169 TTATAGCCATTCTATCT 3-10- TTAtagccattctAtCT 169_47 -19.24 5224 1-1-2 169 TTATAGCCATTCTATCT 2-11- TTatagccattctAtCT 169_48 -18.11 5224 1-1-2 169 TTATAGCCATTCTATCT 1-2-2- TtaTAgccattctAtCT 169_49 -19.37 5224 8-1-1-2 169 TTATAGCCATTCTATCT 3-1-1- TTAtAgccattctatCT 169_50 -19.74 5224 10-2 169 TTATAGCCATTCTATCT 3-12-2 TTAtagccattctatCT 169_51 -19.15 5224 169 TTATAGCCATTCTATCT 2-1-2- TTaTAgccattctatCT 169_52 -20.51 5224 10-2 169 TTATAGCCATTCTATCT 2-1-1- TTaTagccattctatCT 169_53 -18.88 5224 11-2 169 TTATAGCCATTCTATCT 2-2-1- TTatAgccattctatCT 169_54 -18.61 5224 10-2 169 TTATAGCCATTCTATCT 2-13-2 TTatagccattctatCT 169_55 -18.02 5224 169 TTATAGCCATTCTATCT 1-1-3- TtATAgccattctatCT 169_56 -20.18 5224 10-2 169 TTATAGCCATTCTATCT 1-1-2- TtATagccattctatCT 169_57 -18.55 5224 11-2 169 TTATAGCCATTCTATCT 2-9-3- TTatagccattCTAtCT 169_58 -21.75 5224 1-2 169 TTATAGCCATTCTATCT 1-1-1- TtAtagccattCTatCT 169_59 -19.47 5224 8-2-2-2 169 TTATAGCCATTCTATCT 1-2-2- TtaTAgccattCTatCT 169_60 -21.87 5224 6-2-2-2 169 TTATAGCCATTCTATCT 1-1-3- TtATAgccattCtAtCT 169_61 -21.25 5224 6-1-1- 1-1-2 169 TTATAGCCATTCTATCT 3-8-1- TTAtagccattCtaTCT 169_62 -21.25 5224 2-3 170 ATTTAAATTTCCAAACATT 2-13-4 ATttaaatttccaaaCATT 170_1 -16.82 5427 171 GCTAATTTAAATTTCC 4-10-2 GCTAatttaaatttCC 171_1 -18.50 5434 172 ATCAATATCTTCTCAC 3-10-3 ATCaatatcttctCAC 172_1 -17.10 5785 173 TATCAATATCTTCTCA 2-10-4 TAtcaatatcttCTCA 173_1 -17.55 5786 174 CTACAAATTCAATTTACT 2-12-4 CTacaaattcaattTACT 174_1 -17.38 6341 175 TCTTACTCTGACTTTCCA 2-14-2 TCttactctgactttcCA 175_1 -21.47 6694 176 TCTTACTCTGACTTTCC 2-12-3 TCttactctgacttTCC 176_1 -21.53 6695 177 AAATTTCCAAACCTTTC 2-11-4 AAatttccaaaccTTTC 177_1 -16.30 6958 178 CTTCTTGTTTATCCCAA 2-11-4 CTtcttgtttatcCCAA 178_1 -22.77 7159 179 TTCTTGTTTATCCCAA 2-10-4 TTcttgtttatcCCAA 179_1 -20.17 7159 180 ATGCTTCTAACTAACA 4-10-2 ATGCttctaactaaCA 180_1 -19.21 7720 181 CTTTAATGCTTCTAACT 4-11-2 CTTTaatgcttctaaCT 181_1 -18.49 7724 182 CCTTTAATGCTTCTAAC 2-11-4 CCtttaatgcttcTAAC 182_1 -20.06 7725 183 CTTTAATGCTTCTAAC 2-10-4 CTttaatgcttcTAAC 183_1 -16.07 7725 184 TTCCTTTAATGCTTCTA 4-11-2 TTCCtttaatgcttcTA 184_1 -21.59 7727 185 TATACCTTTCTTTAACCCT 2-15-2 TAtacctttctttaaccCT 185_1 -22.03 8117 186 ATACCTTTCTTTAACCC 4-11-2 ATACctttctttaacCC 186_1 -22.68 8118 187 TTATACCTTTCTTTAACC 4-12-2 TTATacctttctttaaCC 187_1 -21.52 8119 188 TTTATACCTTTCTTTAAC 2-12-4 TTtatacctttcttTAAC 188_1 -17.01 8120 189 TCAAGAATTCTCTCCTT 2-11-4 TCaagaattctctCCTT 189_1 -21.29 8571 190 TTCAAGAATTCTCTCC 2-10-4 TTcaagaattctCTCC 190_1 -19.38 8573 191 CTTCAAGAATTCTCTC 2-10-4 CTtcaagaattcTCTC 191_1 -18.00 8574 192 TCTTCAAGAATTCTCT 2-10-4 TCttcaagaattCTCT 192_1 -18.46 8575 193 ATCTTCAAGAATTCTC 3-10-3 ATCttcaagaattCTC 193_1 -17.04 8576 194 TTTCTTACTATCTTCA 4-10-2 TTTCttactatcttCA 194_1 -17.47 8585 195 CCTTTAGCATTTCTATT 2-11-4 CCtttagcatttcTATT 195_1 -21.72 8819 196 TCCTTTAGCATTTCTAT 3-11-3 TCCtttagcatttcTAT 196_1 -22.39 8820 197 GTTCTCTTTATTTCTTCT 2-12-4 GTtctctttatttcTTCT 197_1 -21.76 8887 198 TTTACTGTCAACTCCT 2-10-4 TTtactgtcaacTCCT 198_1 -20.83 9150 199 TTTCCAATGAATCTAT 2-10-4 TTtccaatgaatCTAT 199_1 -16.61 9201 200 CCTTTCCAATGAATCTA 2-11-4 CCtttccaatgaaTCTA 200_1 -22.34 9202 201 CTTTCCAATGAATCTA 2-10-4 CTttccaatgaaTCTA 201_1 -18.34 9202 202 CCTTTCCAATGAATCT 3-10-3 CCTttccaatgaaTCT 202_1 -21.30 9203 203 TTATACCCTTTCCAAT 2-10-4 TTataccctttcCAAT 203_1 -19.61 9209 204 GTTTATACCCTTTCCAA 3-11-3 GTTtataccctttcCAA 204_1 -21.88 9210 205 TTTATACCCTTTCCAA 2-10-4 TTtataccctttCCAA 205_1 -20.50 9210 206 GTTTATACCCTTTCCA 2-11-3 GTttataccctttCCA 206_1 -22.69 9211 207 TGTTTATACCCTTTCCA 3-12-2 TGTttataccctttcCA 207_1 -22.80 9211 208 ACTGTTTATACCCTTTCC 2-14-2 ACtgtttataccctttCC 208_1 -22.96 9212 208 ACTGTTTATACCCTTTCC 1-11- ActgtttataccCtttCC 208_2 -22.45 9212 1-3-2 208 ACTGTTTATACCCTTTCC 1-2-1- ActGtttataccctTtCC 208_3 -22.17 9212 10-1-1- 2 208 ACTGTTTATACCCTTTCC 1-2-1- ActGtTtataccctttCC 208_4 -22.17 9212 1-1-10- 2 208 ACTGTTTATACCCTTTCC 1-2-1- ActGtttataccctttCC 208_5 -21.87 9212 12-2 208 ACTGTTTATACCCTTTCC 1-3-1- ActgTttataccctttCC 208_6 -22.22 9212 11-2 208 ACTGTTTATACCCTTTCC 1-15-2 ActgtttataccctttCC 208_7 -21.56 9212 209 ACTGTTTATACCCTTTC 4-11-2 ACTGtttatacccttTC 209_1 -21.65 9213 209 ACTGTTTATACCCTTTC 1-11- ActgtttataccCttTC 209_2 -18.25 9213 1-2-2 209 ACTGTTTATACCCTTTC 1-1-1- AcTgtttatacCcTtTC 209_3 -19.56 9213 8-1-1- 1-1-2 209 ACTGTTTATACCCTTTC 1-2-1- ActGtttatacccTTTC 209_4 -19.51 9213 9-4 209 ACTGTTTATACCCTTTC 1-3-1- ActgTttatacCctTTC 209_5 -19.51 9213 6-1-2-3 209 ACTGTTTATACCCTTTC 2-9-1- ACtgtttatacCcttTC 209_6 -19.43 9213 3-2 209 ACTGTTTATACCCTTTC 1-2-1- ActGtttatacCcttTC 209_7 -18.35 9213 7-1-3-2 209 ACTGTTTATACCCTTTC 1-3-1- ActgTttatacccTtTC 209_8 -18.53 9213 8-1-1-2 209 ACTGTTTATACCCTTTC 1-11- ActgtttataccCtTTC 209_9 -19.06 9213 1-1-3 209 ACTGTTTATACCCTTTC 2-10- ACtgtttataccCttTC 209_10 -19.64 9213 1-2-2 210 AACTGTTTATACCCTTT 4-11-2 AACTgtttataccctTT 210_1 -19.51 9214 211 TATGACTCCAATAATC 3-10-3 TATgactccaataATC 211_1 -16.57 10832 212 CTCCTTTATGACTCCAA 4-11-2 CTCCtttatgactccAA 212_1 -22.74 10837 213 CTCCTTTATGACTCCA 3-11-2 CTCctttatgactcCA 213_1 -21.50 10838 214 CCATTATTTCTTAAATA 4-11-2 CCATtatttcttaaaTA 214_1 -17.56 10877 215 ATTTCATATTACTAACTA 2-12-4 ATttcatattactaACTA 215_1 -16.64 11434 216 CATTTCATATTACTAACT 3-12-3 CATttcatattactaACT 216_1 -17.70 11435 217 TCATTTCATATTACTAAC 4-12-2 TCATttcatattactaAC 217_1 -16.72 11436 218 ATCATTTCATATTACTA 3-11-3 ATCatttcatattaCTA 218_1 -17.23 11438 219 TTATCATTTCATATTACT 4-12-2 TTATcatttcatattaCT 219_1 -17.77 11439 220 TGTACTTTCCTTTACCA 2-13-2 TGtactttcctttacCA 220_1 -20.37 11464 221 TATACACCATCATTATA 4-11-2 TATAcaccatcattaTA 221_1 -18.48 11507 222 TTATACACCATCATTAT 3-11-3 TTAtacaccatcatTAT 222_1 -17.83 11508 223 TATTTATACACCATCAT 3-11-3 TATttatacaccatCAT 223_1 -18.54 11511 224 TTATTTATACACCATC 2-10-4 TTatttatacacCATC 224_1 -16.60 11513 225 AATTATTTATACACCAT 2-11-4 AAttatttatacaCCAT 225_1 -16.82 11514 226 CATGACACTTACATAA 3-10-3 CATgacacttacaTAA 226_1 -16.26 11736 227 AGTTCACTACTATTAC 3-10-3 AGTtcactactatTAC 227_1 -17.55 12361 228 ATAAGCTTACCTCATA 2-10-4 ATaagcttacctCATA 228_1 -19.32 12794 229 TATAAGCTTACCTCAT 3-10-3 TATaagcttacctCAT 229_1 -19.32 12795 230 ATATAAGCTTACCTCA 4-10-2 ATATaagcttacctCA 230_1 -19.32 12796 231 CTTCCCTTTGATAACAT 3-11-3 CTTccctttgataaCAT 231_1 -21.19 12894 232 TTCCCTTTGATAACAT 4-10-2 TTCCctttgataacAT 232_1 -19.27 12894 233 CCTTCCCTTTGATAACA 2-12-3 CCttccctttgataACA 233_1 -23.06 12895 234 CTTCCCTTTGATAACA 4-10-2 CTTCcctttgataaCA 234_1 -20.51 12895 235 CCTTCCCTTTGATAAC 3-11-2 CCTtccctttgataAC 235_1 -20.96 12896 236 TTGATTCAATTCCCTTA 2-11-4 TTgattcaattccCTTA 236_1 -20.48 13223 236 TTGATTCAATTCCCTTA 2-9-1- TTgattcaattCcCtTA 236_2 -19.54 13223 1-1-1-2 236 TTGATTCAATTCCCTTA 2-10- TTgattcaattcCcTTA 236_3 -19.59 13223 1-1-3 236 TTGATTCAATTCCCTTA 2-1-1- TTgAttcaattcCctTA 236_4 -19.06 13223 8-1-2-2 236 TTGATTCAATTCCCTTA 2-2-1- TTgaTtcaattcCctTA 236_5 -19.00 13223 7-1-2-2 236 TTGATTCAATTCCCTTA 2-9-1- TTgattcaattCcctTA 236_6 -18.65 13223 3-2 236 TTGATTCAATTCCCTTA 1-2-2- TtgATtcaattCCctTA 236_7 -21.37 13223 6-2-2-2 236 TTGATTCAATTCCCTTA 2-1-1- TTgAttcaattCcCtTA 236_8 -20.04 13223 7-1-1- 1-1-2 236 TTGATTCAATTCCCTTA 1-1-2- TtGAttcaattCcCtTA 236_9 -20.10 13223 7-1-1- 1-1-2 236 TTGATTCAATTCCCTTA 1-2-1- TtgAttcaattccCTTA 236_10 -19.67 13223 9-4 236 TTGATTCAATTCCCTTA 1-3-1- TtgaTtcaattCcCtTA 236_11 -18.67 13223 6-1-1- 1-1-2 236 TTGATTCAATTCCCTTA 2-10- TTgattcaattcCctTA 236_12 -18.56 13223 1-2-2 236 TTGATTCAATTCCCTTA 1-2-2- TtgATtcaattcCCtTA 236_13 -21.49 13223 7-2-1-2 236 TTGATTCAATTCCCTTA 1-1-2- TtGAttcaattcCctTA 236_14 -19.13 13223 8-1-2-2 236 TTGATTCAATTCCCTTA 2-11- TTgattcaattccCtTA 236_15 -18.77 13223 1-1-2 236 TTGATTCAATTCCCTTA 1-1-1- TtGaTtcaattccCtTA 236_16 -18.07 13223 1-1-8- 1-1-2 236 TTGATTCAATTCCCTTA 1-1-2- TtGAttcaattCCctTA 236_17 -21.50 13223 7-2-2-2 236 TTGATTCAATTCCCTTA 1-2-1- TtgAttcaattCcCTTA 236_18 -20.44 13223 7-1-1-4 236 TTGATTCAATTCCCTTA 3-8-1- TTGattcaattCcCtTA 236_19 -20.60 13223 1-1-1-2 236 TTGATTCAATTCCCTTA 2-2-1- TTgaTtcaattCcctTA 236_20 -19.09 13223 6-1-3-2 236 TTGATTCAATTCCCTTA 2-2-1- TTgaTtcaattcCCtTA 236_21 -21.49 13223 7-2-1-2 237 ATTGATTCAATTCCCTT 2-11-4 ATtgattcaattcCCTT 237_1 -21.28 13224 237 ATTGATTCAATTCCCTT 3-8-3- ATTgattcaatTCCcTT 237_2 -22.78 13224 1-2 237 ATTGATTCAATTCCCTT 1-1-1- AtTgattcaatTCCcTT 237_3 -21.02 13224 8-3-1-2 237 ATTGATTCAATTCCCTT 1-2-1- AttGattcaattCCcTT 237_4 -19.40 13224 8-2-1-2 237 ATTGATTCAATTCCCTT 1-3-1- AttgAttcaattCCcTT 237_5 -19.74 13224 7-2-1-2 237 ATTGATTCAATTCCCTT 1-2-1- AttGattcaatTCcCTT 237_6 -19.67 13224 7-2-1-3 237 ATTGATTCAATTCCCTT 2-2-1- ATtgAttcaattCcCTT 237_7 -20.27 13224 7-1-1-3 237 ATTGATTCAATTCCCTT 1-1-1- AtTgattcaattCcCTT 237_8 -19.32 13224 9-1-1-3 237 ATTGATTCAATTCCCTT 1-3-1- AttgAttcaattCcCTT 237_9 -19.02 13224 7-1-1-3 237 ATTGATTCAATTCCCTT 1-1-1- AtTgAttcaattCCcTT 237_10 -20.53 13224 1-1-7- 2-1-2 237 ATTGATTCAATTCCCTT 1-2-2- AttGAttcaattCCcTT 237_11 -21.11 13224 7-2-1-2 237 ATTGATTCAATTCCCTT 1-2-1- AttGattcaattCcCTT 237_12 -18.68 13224 8-1-1-3 237 ATTGATTCAATTCCCTT 1-1-2- AtTGattcaattCccTT 237_13 -18.81 13224 8-1-2-2 237 ATTGATTCAATTCCCTT 3-10- ATTgattcaattcCcTT 237_14 -19.42 13224 1-1-2 237 ATTGATTCAATTCCCTT 1-1-2- AtTGattcaattcCCTT 237_15 -21.89 13224 9-4 237 ATTGATTCAATTCCCTT 2-2-1- ATtgAttcaattcCcTT 237_16 -18.61 13224 8-1-1-2 237 ATTGATTCAATTCCCTT 1-2-2- AttGAttcaatTCCcTT 237_17 -22.09 13224 6-3-1-2 237 ATTGATTCAATTCCCTT 1-1-1- AtTgattcaatTCcCTT 237_18 -20.30 13224 8-2-1-3 237 ATTGATTCAATTCCCTT 1-1-1- AtTgattcaattCCcTT 237_19 -20.03 13224 9-2-1-2 237 ATTGATTCAATTCCCTT 1-1-1- AtTgAttcaattCcCTT 237_20 -19.82 13224 1-1-7- 1-1-3 237 ATTGATTCAATTCCCTT 3-1-1- ATTgAttcaattcCcTT 237_21 -19.92 13224 8-1-1-2 238 TTGATTCAATTCCCTT 2-10-4 TTgattcaattcCCTT 238_1 -20.52 13224 239 TATTGATTCAATTCCCT 2-11-4 TAttgattcaattCCCT 239_1 -22.82 13225 239 TATTGATTCAATTCCCT 3-9-2- TATtgattcaatTCcCT 239_2 -21.17 13225 1-2 239 TATTGATTCAATTCCCT 2-9-1- TAttgattcaaTtCcCT 239_3 -19.37 13225 1-1-1-2 239 TATTGATTCAATTCCCT 1-1-2- TaTTgattcaaTTCcCT 239_4 -21.49 13225 7-3-1-2 239 TATTGATTCAATTCCCT 1-3-1- TattGattcaaTTCcCT 239_5 -19.90 13225 6-3-1-2 239 TATTGATTCAATTCCCT 2-9-1- TAttgattcaaTtcCCT 239_6 -20.89 13225 2-3 239 TATTGATTCAATTCCCT 1-10- TattgattcaaTtcCCT 239_7 -19.76 13225 1-2-3 239 TATTGATTCAATTCCCT 1-1-1- TaTtGattcaattCcCT 239_8 -18.41 13225 1-1-8- 1-1-2 239 TATTGATTCAATTCCCT 1-2-2- TatTGattcaattCcCT 239_9 -19.66 13225 8-1-1-2 239 TATTGATTCAATTCCCT 1-2-1- TatTgattcaattCcCT 239_10 -18.60 13225 9-1-1-2 239 TATTGATTCAATTCCCT 2-2-1- TAttGattcaattccCT 239_11 -18.33 13225 10-2 239 TATTGATTCAATTCCCT 1-12-4 TattgattcaattCCCT 239_12 -21.69 13225 239 TATTGATTCAATTCCCT 2-1-1- TAtTgattcaattCcCT 239_13 -19.73 13225 9-1-1-2 239 TATTGATTCAATTCCCT 2-12-3 TAttgattcaattcCCT 239_14 -20.45 13225 239 TATTGATTCAATTCCCT 1-2-1- TatTgattcaattcCCT 239_15 -20.11 13225 10-3 239 TATTGATTCAATTCCCT 1-1-3- TaTTGattcaattccCT 239_16 -19.84 13225 10-2 239 TATTGATTCAATTCCCT 1-1-1- TaTtGattcaaTTCcCT 239_17 -20.34 13225 1-1-6- 3-1-2 239 TATTGATTCAATTCCCT 2-2-1- TAttGattcaaTtCcCT 239_18 -19.54 13225 6-1-1- 1-1-2 239 TATTGATTCAATTCCCT 2-1-1- TAtTgattcaatTCcCT 239_19 -20.72 13225 8-2-1-2 239 TATTGATTCAATTCCCT 1-1-2- TaTTgattcaattCcCT 239_20 -19.55 13225 9-1-1-2 239 TATTGATTCAATTCCCT 2-1-1- TAtTgattcaattcCCT 239_21 -21.24 13225 10-3 240 TATTGATTCAATTCCC 3-10-3 TATtgattcaattCCC 240_1 -20.58 13226 241 GCACATTCTTTCTATAC 3-11-3 GCAcattctttctaTAC 241_1 -21.17 15115 241 GCACATTCTTTCTATAC 1-1-3- GcACAttctttCTatAC 241_2 -20.68 15115 6-2-2-2 241 GCACATTCTTTCTATAC 1-1-1- GcAcAttctttCtaTAC 241_3 -18.46 15115 1-1-6- 1-2-3 241 GCACATTCTTTCTATAC 1-1-2- GcACattctttCtaTAC 241_4 -19.49 15115 7-1-2-3 241 GCACATTCTTTCTATAC 2-9-1- GCacattctttCtatAC 241_5 -18.68 15115 3-2 241 GCACATTCTTTCTATAC 1-1-3- GcACAttctttctATAC 241_6 -20.89 15115 8-4 241 GCACATTCTTTCTATAC 2-2-1- GCacAttctttctaTAC 241_7 -19.66 15115 9-3 241 GCACATTCTTTCTATAC 2-1-1- GCaCattctttctatAC 241_8 -18.39 15115 11-2 241 GCACATTCTTTCTATAC 1-1-3- GcACAttctttctaTAC 241_9 -19.98 15115 9-3 241 GCACATTCTTTCTATAC 3-12-2 GCAcattctttctatAC 241_10 -19.27 15115 241 GCACATTCTTTCTATAC 1-1-1- GcAcAttctttCtATAC 241_11 -19.36 15115 1-1-6- 1-1-4 241 GCACATTCTTTCTATAC 3-8-1- GCAcattctttCtAtAC 241_12 -20.34 15115 1-1-1-2 241 GCACATTCTTTCTATAC 2-1-1- GCaCattctttCtaTAC 241_13 -21.27 15115 7-1-2-3 241 GCACATTCTTTCTATAC 1-2-2- GcaCAttctttctATAC 241_14 -20.33 15115 8-4 241 GCACATTCTTTCTATAC 1-1-3- GcACAttctttctatAC 241_15 -18.08 15115 10-2 242 GAATTTCAACTACTAT 2-10-4 GAatttcaactaCTAT 242_1 -16.13 15258 243 CCATTTATTTCCATTTAT 3-12-3 CCAtttatttccattTAT 243_1 -21.92 15568 244 TTTCCATTTATTTCCATTT 4-13-2 TTTCcatttatttccatTT 244_1 -20.93 15570 244 TTTCCATTTATTTCCATTT 1-4-1- TttccAtttatttCcATTT 244_2 -20.48 15570 7-1-1-4 244 TTTCCATTTATTTCCATTT 2-1-1- TTtCcatttatttcCAtTT 244_3 -21.47 15570 10-2-1- 2 244 TTTCCATTTATTTCCATTT 1-2-1- TttCcAtttatttCcatTT 244_4 -19.43 15570 1-1-7- 1-3-2 244 TTTCCATTTATTTCCATTT 2-2-2- TTtcCAtttatttccatTT 244_5 -20.70 15570 11-2 245 CTTTCCATTTATTTCCAT 3-12-3 CTTtccatttatttcCAT 245_1 -22.31 15572 246 TCTTTCCATTTATTTCCA 4-12-2 TCTTtccatttatttcCA 246_1 -22.74 15573 247 ATCTTTCCATTTATTTCC 3-12-3 ATCtttccatttattTCC 247_1 -22.85 15574 248 TTCCATGCAAACTTTA 4-10-2 TTCCatgcaaacttTA 248_1 -19.01 15722 249 CAGTTTAAATTCACAC 3-10-3 CAGtttaaattcaCAC 249_1 -16.68 16597 250 CTATTCCAGTTTAAAT 4-10-2 CTATtccagtttaaAT 250_1 -16.86 16603 251 TGCAAATACCTCTTCA 4-10-2 TGCAaatacctcttCA 251_1 -21.49 16730 252 CTAAATAGATTCCACT 2-10-4 CTaaatagattcCACT 252_1 -17.95 16849 253 TATTGATATTTACTCT 2-10-4 TAttgatatttaCTCT 253_1 -16.32 17089 254 CCTTAGTATTACAATT 4-10-2 CCTTagtattacaaTT 254_1 -17.43 17401 255 CTATTCAATAAACTAAACA 4-13-2 CTATtcaataaactaaaCA 255_1 -16.45 24290 256 CAGCTATTCAATAAAC 4-10-2 CAGCtattcaataaAC 256_1 -16.94 24296 257 TATAGACCCAAACTAT 3-10-3 TATagacccaaacTAT 257_1 -18.15 24811 258 TAATCCCATACATCTAT 2-11-4 TAatcccatacatCTAT 258_1 -20.45 25032 259 ATAATCCCATACATCTA 3-11-3 ATAatcccatacatCTA 259_1 -20.45 25033 260 ATCTCAACTACCATTT 4-10-2 ATCTcaactaccatTT 260_1 -18.14 25250 261 AATCTCAACTACCATT 4-10-2 AATCtcaactaccaTT 261_1 -16.76 25251 262 ACAACTTCTATCATAC 3-10-3 ACAacttctatcaTAC 262_1 -16.33 25718 263 GAACAACTTCTATCAT 2-10-4 GAacaacttctaTCAT 263_1 -16.94 25720 264 TGAACAACTTCTATCA 3-10-3 TGAacaacttctaTCA 264_1 -17.36 25721 265 TACACAAATACTTAAATCA 4-13-2 TACAcaaatacttaaatCA 265_1 -16.93 26331 266 TTAAGCTTTCACCTAT 2-10-4 TTaagctttcacCTAT 266_1 -19.36 27165 267 AAACTCTTGCATCTACT 2-13-2 AAactcttgcatctaCT 267_1 -16.65 27248 268 AAATTTCTCAACCTAAATTT 2-14-4 AAatttctcaacctaaATTT 268_1 -16.78 29330 269 CCAACATAGATCCTCT 2-10-4 CCaacatagatcCTCT 269_1 -22.49 29635 270 TCCAACATAGATCCTCT 2-11-4 TCcaacatagatcCTCT 270_1 -22.81 29635 271 CTCCAACATAGATCCTC 3-11-3 CTCcaacatagatcCTC 271_1 -22.81 29636 272 TCCAACATAGATCCTC 2-10-4 TCcaacatagatCCTC 272_1 -21.69 29636 273 CTCCAACATAGATCCT 3-10-3 CTCcaacatagatCCT 273_1 -22.68 29637 274 TCTCCAACATAGATCCT 4-11-2 TCTCcaacatagatcCT 274_1 -22.81 29637 275 ATTCTCAATTGCACTT 4-10-2 ATTCtcaattgcacTT 275_1 -17.90 29661 276 TATTCTCAATTGCACTT 4-11-2 TATTctcaattgcacTT 276_1 -18.54 29661 277 TCACCTAATAGCACCA 2-10-4 TCacctaatagcACCA 277_1 -21.99 29684 278 TTCACCTAATAGCACCA 2-11-4 TTcacctaatagcACCA 278_1 -22.53 29684 279 CATTATTATTTAACCTT 2-11-4 CAttattatttaaCCTT 279_1 -17.83 30455 280 ACATTATTATTTAACCT 3-11-3 ACAttattatttaaCCT 280_1 -18.05 30456 281 TACATTATTATTTAACC 4-11-2 TACAttattatttaaCC 281_1 -16.80 30457 282 CATTTACATTATTATTTAAC 2-14-4 CAtttacattattattTAAC 282_1 -16.44 30458 283 CTCATTTACATTATTATT 4-12-2 CTCAtttacattattaTT 283_1 -17.33 30462 284 TATCTCATTTACATTATT 4-12-2 TATCtcatttacattaTT 284_1 -17.62 30465 285 ATCATTCTCAACAATTA 4-11-2 ATCAttctcaacaatTA 285_1 -17.04 30601 285 ATCATTCTCAACAATTA 4-7-6 ATCAttctcaaCAATTA 285_2 -21.48 30601 285 ATCATTCTCAACAATTA 1-1-3- AtCATtctcaaCAATTA 285_3 -20.80 30601 6-6 285 ATCATTCTCAACAATTA 5-6-2- ATCATtctcaaCAatTA 285_4 -20.46 30601 2-2 285 ATCATTCTCAACAATTA 4-7-1- ATCAttctcaaCaATTA 285_5 -19.80 30601 1-4 285 ATCATTCTCAACAATTA 5-7-1- ATCATtctcaacAaTTA 285_6 -19.31 30601 1-3 285 ATCATTCTCAACAATTA 5-6-3- ATCATtctcaaCAAtTA 285_7 -20.97 30601 1-2 285 ATCATTCTCAACAATTA 4-7-2- ATCAttctcaaCAaTTA 285_8 -20.16 30601 1-3 285 ATCATTCTCAACAATTA 5-6-1- ATCATtctcaaCaATTA 285_9 -21.05 30601 1-4 285 ATCATTCTCAACAATTA 5-6-1- ATCATtctcaaCaAtTA 285_10 -19.29 30601 1-1-1-2 285 ATCATTCTCAACAATTA 1-1-3- AtCATtctcaacAATTA 285_11 -18.70 30601 7-5 286 AAGATCATTCTCAACA 4-10-2 AAGAtcattctcaaCA 286_1 -17.15 30605 287 TCTCAAAGATCATTCTC 3-11-3 TCTcaaagatcattCTC 287_1 -19.02 30609 288 TCTCAAAGATCATTCT 4-10-2 TCTCaaagatcattCT 288_1 -17.81 30610 289 ACTTAATTATACTTCC 4-10-2 ACTTaattatacttCC 289_1 -17.28 30667 290 TACACTTAATTATACTTC 2-12-4 TAcacttaattataCTTC 290_1 -16.87 30668 291 TTACACTTAATTATACTT 3-12-3 TTAcacttaattataCTT 291_1 -16.20 30669 292 TTTACACTTAATTATACT 2-12-4 TTtacacttaattaTACT 292_1 -16.23 30670 293 CTATTTAATTTACACTT 3-11-3 CTAtttaatttacaCTT 293_1 -16.26 30679 294 TATCTATTTAATTTACAC 3-12-3 TATctatttaatttaCAC 294_1 -16.06 30681 295 TTTATCTATTTAATTTACA 4-13-2 TTTAtctatttaatttaCA 295_1 -16.34 30682 296 CTCTGCTTATAACTTT 4-10-2 CTCTgcttataactTT 296_1 -18.51 30699 297 CCTCTGCTTATAACTT 3-10-3 CCTctgcttataaCTT 297_1 -21.29 30700 298 TCCTCTGCTTATAACTT 3-12-2 TCCtctgcttataacTT 298_1 -20.86 30700 299 TCCTCTGCTTATAACT 3-11-2 TCCtctgcttataaCT 299_1 -20.70 30701 300 TTCCTCTGCTTATAACT 3-12-2 TTCctctgcttataaCT 300_1 -20.03 30701 301 TTTCCTCTGCTTATAAC 4-11-2 TTTCctctgcttataAC 301_1 -19.20 30702 302 TACTATACTTTCCTCT 2-10-4 TActatactttcCTCT 302_1 -20.07 30711 303 TTCTACTATACTTTCC 4-10-2 TTCTactatactttCC 303_1 -19.55 30714 304 AGTTCTACTATACTTTC 4-11-2 AGTTctactatacttTC 304_1 -18.49 30715 304 AGTTCTACTATACTTTC 1-10-6 AgttctactatACTTTC 304_2 -18.76 30715 304 AGTTCTACTATACTTTC 1-1-2- AgTTctactatAcTTTC 304_3 -18.23 30715 7-1-1-4 304 AGTTCTACTATACTTTC 3-8-2- AGTtctactatACttTC 304_4 -19.19 30715 2-2 304 AGTTCTACTATACTTTC 2-2-1- AGttCtactatAcTTTC 304_5 -19.07 30715 6-1-1-4 304 AGTTCTACTATACTTTC 1-2-2- AgtTCtactatacTTTC 304_6 -18.46 30715 8-4 304 AGTTCTACTATACTTTC 3-10- AGTtctactatacTtTC 304_7 -18.12 30715 1-1-2 304 AGTTCTACTATACTTTC 3-11-3 AGTtctactatactTTC 304_8 -18.42 30715 304 AGTTCTACTATACTTTC 3-1-1- AGTtCtactatacttTC 304_9 -18.58 30715 10-2 304 AGTTCTACTATACTTTC 2-1-2- AGtTCtactatacttTC 304_10 -18.02 30715 10-2 304 AGTTCTACTATACTTTC 1-2-2- AgtTCtactatACtTTC 304_11 -19.02 30715 6-2-1-3 304 AGTTCTACTATACTTTC 2-1-2- AGtTCtactatActtTC 304_12 -18.22 30715 6-1-3-2 304 AGTTCTACTATACTTTC 2-2-1- AGttCtactataCTtTC 304_13 -19.22 30715 7-2-1-2 304 AGTTCTACTATACTTTC 3-1-1- AGTtCtactataCtTTC 304_14 -20.39 30715 7-1-1-3 304 AGTTCTACTATACTTTC 1-1-1- AgTtCtactatacTTTC 304_15 -18.13 30715 1-1-8-4 305 GTTCTACTATACTTTC 4-10-2 GTTCtactatacttTC 305_1 -17.48 30715 306 CATTATATTTAAACTATCA 4-13-2 CATTatatttaaactatCA 306_1 -16.93 31630 307 CACATTATATTTAAACTAT 2-13-4 CAcattatatttaaaCTAT 307_1 -17.11 31632 308 ACACATTATATTTAAACTA 3-13-3 ACAcattatatttaaaCTA 308_1 -17.09 31633 309 ACCACCTAAGACCTCAA 2-11-4 ACcacctaagaccTCAA 309_1 -22.49 32755 310 CCACCTAAGACCTCAA 2-10-4 CCacctaagaccTCAA 310_1 -22.63 32755 311 ACCACCTAAGACCTCA 2-11-3 ACcacctaagaccTCA 311_1 -21.74 32756 312 ACCTTAAGTAACATTT 4-10-2 ACCTtaagtaacatTT 312_1 -16.82 33366 313 CACCTTAAGTAACATT 4-10-2 CACCttaagtaacaTT 313_1 -18.05 33367 314 CCACCTTAAGTAACAT 3-10-3 CCAccttaagtaaCAT 314_1 -20.70 33368 315 ACCACCTTAAGTAACA 4-10-2 ACCAccttaagtaaCA 315_1 -20.68 33369 316 TTATTAACCACCTTAA 3-10-3 TTAttaaccacctTAA 316_1 -16.19 33375 317 CATTATTAACCACCTT 2-10-4 CAttattaaccaCCTT 317_1 -19.92 33377 318 ACATTATTAACCACCT 3-10-3 ACAttattaaccaCCT 318_1 -20.14 33378 319 ACCAATTATACTTACAA 3-11-3 ACCaattatacttaCAA 319_1 -17.16 36606 320 AACCAATTATACTTACA 4-11-2 AACCaattatacttaCA 320_1 -17.16 36607 321 CAAATACAGATTATCC 2-10-4 CAaatacagattATCC 321_1 -16.44 38092 322 TTTACATTCCCATCATC 2-11-4 TTtacattcccatCATC 322_1 -21.08 38297 323 CACACCTATTATATAAT 4-11-2 CACAcctattatataAT 323_1 -17.02 39173 324 TCACACCTATTATATAA 3-11-3 TCAcacctattataTAA 324_1 -17.02 39174 325 CTTCACACCTATTATATA 2-12-4 CTtcacacctattaTATA 325_1 -20.65 39175 326 ACTTCACACCTATTATAT 3-12-3 ACTtcacacctattaTAT 326_1 -20.46 39176 327 GCTCACACTAATTATT 2-10-4 GCtcacactaatTATT 327_1 -18.72 39228 328 ATGCTCACACTAATTA 4-10-2 ATGCtcacactaatTA 328_1 -19.38 39230 329 AATGCTCACACTAATT 4-10-2 AATGctcacactaaTT 329_1 -16.21 39231 330 AAACTGTACACCTACT 2-10-4 AAactgtacaccTACT 330_1 -17.99 39563 331 GTTTCCATCTACTATTA 2-11-4 GTttccatctactATTA 331_1 -19.78 39808 332 TTTCCATCTACTATTA 4-10-2 TTTCcatctactatTA 332_1 -17.25 39808 333 TGACATAACCATATAC 3-10-3 TGAcataaccataTAC 333_1 -16.63 39931 334 GCTCCCAAACAACTAA 2-12-2 GCtcccaaacaactAA 334_1 -17.55 41114 335 CCTCAATACTCTACTT 4-10-2 CCTCaatactctacTT 335_1 -20.30 41444 336 GACCTCAATACTCTACT 3-11-3 GACctcaatactctACT 336_1 -21.01 41445 337 GACCTCAATACTCTAC 4-10-2 GACCtcaatactctAC 337_1 -20.02 41446 338 TACTAAACATACACATA 4-11-2 TACTaaacatacacaTA 338_1 -16.12 41725 339 CTACTAAACATACACAT 3-11-3 CTActaaacatacaCAT 339_1 -17.31 41726 340 TTCTACTAAACATACAC 3-11-3 TTCtactaaacataCAC 340_1 -16.07 41728 341 TACCAATAGTTACCTT 2-10-4 TAccaatagttaCCTT 341_1 -20.03 42167 342 CTTACCAATAGTTACCT 3-11-3 CTTaccaatagttaCCT 342_1 -22.29 42168 343 TTACCAATAGTTACCT 3-10-3 TTAccaatagttaCCT 343_1 -20.03 42168 344 CTTACCAATAGTTACC 4-10-2 CTTAccaatagttaCC 344_1 -20.03 42169 345 TCTTACCAATAGTTACC 4-11-2 TCTTaccaatagttaCC 345_1 -21.30 42169 346 TCAAAGCACACCACCAC 2-12-3 TCaaagcacaccacCAC 346_1 -21.69 42287 347 ATTCAAAGCACACCACC 2-12-3 ATtcaaagcacaccACC 347_1 -21.00 42289 348 AGACTAATCCTCTTAA 3-10-3 AGActaatcctctTAA 348_1 -17.72 43452 349 TAGACTAATCCTCTTA 4-10-2 TAGActaatcctctTA 349_1 -19.20 43453 350 CCCATTTCTAACATTTAC 3-12-3 CCCatttctaacattTAC 350_1 -22.93 43562 351 ACCCATTTCTAACATT 4-10-2 ACCCatttctaacaTT 351_1 -20.64 43565 352 AACCCATTTCTAACAT 4-10-2 AACCcatttctaacAT 352_1 -18.25 43566 353 CCTCAACTTCACCAAT 2-10-4 CCtcaacttcacCAAT 353_1 -21.73 43634 354 ACTGATTTCCTTAAAC 4-10-2 ACTGatttccttaaAC 354_1 -16.67 44180 355 CACTGATTTCCTTAAAC 4-11-2 CACTgatttccttaaAC 355_1 -18.91 44180 356 CCACTGATTTCCTTAAA 4-11-2 CCACtgatttccttaAA 356_1 -20.91 44181 357 ACCACTGATTTCCTTA 2-10-4 ACcactgatttcCTTA 357_1 -20.98 44183 358 CACCACTGATTTCCTT 3-10-3 CACcactgatttcCTT 358_1 -22.04 44184 359 CTCTGCAATACACCAA 2-10-4 CTctgcaatacaCCAA 359_1 -20.90 44439 360 ACTCTGCAATACACCA 3-10-3 ACTctgcaatacaCCA 360_1 -22.19 44440 361 TACTCTGCAATACACCA 2-11-4 TActctgcaatacACCA 361_1 -22.32 44440 361 TACTCTGCAATACACCA 1-1-1- TaCtctgcaatacAcCA 361_2 -19.29 44440 10-1-1- 2 361 TACTCTGCAATACACCA 1-3-1- TactCtgcaatacAcCA 361_3 -19.28 44440 8-1-1-2 361 TACTCTGCAATACACCA 1-10- TactctgcaatAcacCA 361_4 -18.35 44440 1-3-2 361 TACTCTGCAATACACCA 2-10- TActctgcaataCACCA 361_5 -21.63 44440 2-1-2 361 TACTCTGCAATACACCA 1-13-3 TactctgcaatacaCCA 361_6 -20.54 44440 361 TACTCTGCAATACACCA 2-10- TActctgcaataCacCA 361_7 -20.06 44440 1-2-2 361 TACTCTGCAATACACCA 1-1-1- TaCtctgcaatacacCA 361_8 -19.14 44440 12-2 361 TACTCTGCAATACACCA 1-2-2- TacTCtgcaatacacCA 361_9 -20.33 44440 10-2 361 TACTCTGCAATACACCA 1-3-1- TactCtgcaatacacCA 361_10 -19.13 44440 10-2 362 TACTCTGCAATACACC 2-10-4 TActctgcaataCACC 362_1 -21.12 44441 362 TACTCTGCAATACACC 1-1-1- TaCtctgcaatacaCC 362_2 -18.23 44441 11-2 362 TACTCTGCAATACACC 1-1-1- TaCtctgcaatacACC 362_3 -18.78 44441 10-3 362 TACTCTGCAATACACC 1-3-1- TactCtgcaataCACC 362_4 -20.87 44441 7-4 362 TACTCTGCAATACACC 3-11-2 TACtctgcaatacaCC 362_5 -19.86 44441 362 TACTCTGCAATACACC 2-2-1 TActCtgcaatacaCC 362_6 -19.44 44441 9-2 362 TACTCTGCAATACACC 2-12-2 TActctgcaatacaCC 362_7 -18.47 44441 362 TACTCTGCAATACACC 1-2-2- TacTCtgcaatacaCC 362_8 -19.42 44441 9-2 362 TACTCTGCAATACACC 2-1-2- TACTCtgcaatacaCC 362_9 -20.64 44441 9-2 362 TACTCTGCAATACACC 1-3-1- TactCtgcaatacaCC 362_10 -18.22 44441 9-2 363 TTACTCTGCAATACACC 2-11-4 TTactctgcaataCACC 363_1 -21.71 44441 364 TTACTCTGCAATACAC 3-10-3 TTActctgcaataCAC 364_1 -17.75 44442 365 TTTACTCTGCAATACAC 3-11-3 TTTactctgcaataCAC 365_1 -18.34 44442 366 CTTTACTCTGCAATACA 2-11-4 CTttactctgcaaTACA 366_1 -20.23 44443 367 TTTACTCTGCAATACA 2-10-4 TTtactctgcaaTACA 367_1 -17.56 44443 368 GACCACACTTTCTACCA 2-13-2 GAccacactttctacCA 368_1 -21.72 44477 369 GACCACACTTTCTACC 2-12-2 GAccacactttctaCC 369_1 -20.81 44478 370 AAGAAACACCCTTCCA 2-10-4 AAgaaacaccctTCCA 370_1 -21.48 44776 371 ATCTGCTACATATTCTT 4-11-2 ATCTgctacatattcTT 371_1 -19.88 45216 372 ATCTGCTACATATTCT 4-10-2 ATCTgctacatattCT 372_1 -19.71 45217 373 CATCTGCTACATATTCT 4-11-2 CATCtgctacatattCT 373_1 -21.32 45217 374 CATCTGCTACATATTC 4-10-2 CATCtgctacatatTC 374_1 -18.82 45218 375 TTCAACCCTAATCACT 4-10-2 TTCAaccctaatcaCT 375_1 -19.99 45246 376 ATTCAACCCTAATCAC 2-10-4 ATtcaaccctaaTCAC 376_1 -18.67 45247 377 CATTCAACCCTAATCA 3-10-3 CATtcaaccctaaTCA 377_1 -19.93 45248 378 GCATTCAACCCTAATCA 3-12-2 GCAttcaaccctaatCA 378_1 -22.56 45248 379 AGCATTCAACCCTAATC 4-11-2 AGCAttcaaccctaaTC 379_1 -22.98 45249 380 GCATTCAACCCTAATC 4-10-2 GCATtcaaccctaaTC 380_1 -21.63 45249 381 AGCATTCAACCCTAAT 4-10-2 AGCAttcaaccctaAT 381_1 -21.62 45250 382 CAGCATTCAACCCTAAT 3-12-2 CAGcattcaaccctaAT 382_1 -21.12 45250 383 TTAAATCCAGCATTCA 3-10-3 TTAaatccagcatTCA 383_1 -18.08 45258 384 CTCCATATTTAAATCC 4-10-2 CTCCatatttaaatCC 384_1 -20.02 45266 385 GCTCCATATTTAAATCC 4-11-2 GCTCcatatttaaatCC 385_1 -22.84 45266 386 GCTCCATATTTAAATC 4-10-2 GCTCcatatttaaaTC 386_1 -18.78 45267 387 AGCTCCATATTTAAAT 4-10-2 AGCTccatatttaaAT 387_1 -18.62 45268 388 TAAGCTCCATATTTAA 3-10-3 TAAgctccatattTAA 388_1 -16.08 45270 389 CCTAAGCTCCATATTTA 3-11-3 CCTaagctccatatTTA 389_1 -22.65 45271 390 CTAAGCTCCATATTTA 4-10-2 CTAAgctccatattTA 390_1 -18.81 45271 391 CCTAAGCTCCATATTT 4-10-2 CCTAagctccatatTT 391_1 -21.57 45272 392 TCTACCCTAAATTCCC 2-11-3 TCtaccctaaattCCC 392_1 -23.00 45560 393 CACATCTTGTATACAA 3-10-3 CACatcttgtataCAA 393_1 -16.65 45627 394 ACACATCTTGTATACA 4-10-2 ACACatcttgtataCA 394_1 -17.95 45628 395 CTACACATCTTGTATAC 3-11-3 CTAcacatcttgtaTAC 395_1 -19.13 45629 396 TACACATCTTGTATAC 3-10-3 TACacatcttgtaTAC 396_1 -16.73 45629 397 CTTGACTACACATCTT 3-10-3 CTTgactacacatCTT 397_1 -18.89 45635 398 CTCTACAACAGTCCCA 3-11-2 CTCtacaacagtccCA 398_1 -22.06 45709 399 TCTCTACAACAGTCCCA 2-13-2 TCtctacaacagtccCA 399_1 -21.70 45709 400 ATAACATTACTCTTAACA 3-12-3 ATAacattactcttaACA 400_1 -17.03 46215 401 TTTGACATTCCATCTCC 2-12-3 TTtgacattccatcTCC 401_1 -21.62 46256 402 CTTTGACATTCCATCTC 2-11-4 CTttgacattccaTCTC 402_1 -21.88 46257 403 TCTTTGACATTCCATCTC 4-12-2 TCTTtgacattccatcTC 403_1 -22.41 46257 404 TTTGACATTCCATCTC 3-10-3 TTTgacattccatCTC 404_1 -19.40 46257 405 ATCTTTGACATTCCATC 2-11-4 ATctttgacattcCATC 405_1 -20.53 46259 406 TATCTTTGACATTCCAT 2-11-4 TAtctttgacattCCAT 406_1 -21.32 46260 407 TACTATCTTTGACATTC 4-11-2 TACTatctttgacatTC 407_1 -18.39 46263 408 TACTATCTTTGACATT 4-10-2 TACTatctttgacaTT 408_1 -16.84 46264 409 CTGTATACACCATCCC 2-12-2 CTgtatacaccatcCC 409_1 -21.84 46392 410 TCTGTATACACCATCC 4-10-2 TCTGtatacaccatCC 410_1 -22.73 46393 411 TTTCTGACTCCCTATCC 2-13-2 TTtctgactccctatCC 411_1 -22.48 46420 412 CCTATGTTAATACTTTC 4-11-2 CCTAtgttaatacttTC 412_1 -19.53 46505 413 CTATGTTAATACTTTC 4-10-2 CTATgttaatacttTC 413_1 -16.09 46505 414 CCTATGTTAATACTTT 4-10-2 CCTAtgttaatactTT 414_1 -17.85 46506 415 TCCTATGTTAATACTT 3-10-3 TCCtatgttaataCTT 415_1 -18.47 46507 416 ATCCTATGTTAATACT 4-10-2 ATCCtatgttaataCT 416_1 -18.71 46508 417 ATTTCATTAAGTCACCC 3-11-3 ATTtcattaagtcaCCC 417_1 -22.16 47364 418 ATTTCATTAAGTCACC 2-10-4 ATttcattaagtCACC 418_1 -18.79 47365 419 CTCTCCTCAAGATCAAC 3-11-3 CTCtcctcaagatcAAC 419_1 -20.29 48110 420 CTCTCCTCAAGATCAA 3-10-3 CTCtcctcaagatCAA 420_1 -20.33 48111 421 CCATACAGTATATACA 4-10-2 CCATacagtatataCA 421_1 -19.53 48186 422 CAACTATTATCTTCTT 2-10-4 CAactattatctTCTT 422_1 -16.38 48221 423 ACAACTATTATCTTCT 3-10-3 ACAactattatctTCT 423_1 -16.60 48222 424 TTGCTTCCAATTTATTT 4-11-2 TTGCttccaatttatTT 424_1 -19.93 50282 425 ATCTCATGACCACCTAA 3-11-3 ATCtcatgaccaccTAA 425_1 -21.74 51241 425 ATCTCATGACCACCTAA 1-1-1- AtCtcatgaccaCCtAA 425_2 -21.11 51241 9-2-1-2 425 ATCTCATGACCACCTAA 1-1-1- AtCtcatgaccAccTAA 425_3 -19.96 51241 8-1-2-3 425 ATCTCATGACCACCTAA 1-12-4 AtctcatgaccacCTAA 425_4 -20.40 51241 425 ATCTCATGACCACCTAA 3-10- ATCtcatgaccacCtAA 425_5 -20.66 51241 1-1-2 425 ATCTCATGACCACCTAA 1-1-1- AtCtcatgaccacCtAA 425_6 -18.72 51241 10-1-1- 2 425 ATCTCATGACCACCTAA 1-1-1- AtCtcatgaccaCcTAA 425_7 -20.59 51241 9-1-1-3 425 ATCTCATGACCACCTAA 1-2-2- AtcTCatgaccaCcTAA 425_8 -21.48 51241 7-1-1-3 425 ATCTCATGACCACCTAA 1-3-1- AtctCatgaccacCTAA 425_9 -21.07 51241 8-4 425 ATCTCATGACCACCTAA 1-1-3- AtCTCatgaccacCtAA 425_10 -21.27 51241 8-1-1-2 426 TCTCATGACCACCTAA 2-10-4 TCtcatgaccacCTAA 426_1 -21.25 51241 427 ATCTCATGACCACCTA 3-10-3 ATCtcatgaccacCTA 427_1 -22.56 51242 428 TATCTCATGACCACCTA 2-12-3 TAtctcatgaccacCTA 428_1 -21.88 51242 429 TTTATCTCATGACCACC 2-11-4 TTtatctcatgacCACC 429_1 -22.37 51244 430 TTTATCTCATGACCAC 2-10-4 TTtatctcatgaCCAC 430_1 -19.56 51245 431 ATTCTTACCGTCTTTA 4-10-2 ATTCttaccgtcttTA 431_1 -19.52 51358 432 TATTCTTACCGTCTTTA 3-11-3 TATtcttaccgtctTTA 432_1 -20.10 51358 433 TATTCTTACCGTCTTT 2-10-4 TAttcttaccgtCTTT 433_1 -19.30 51359 434 TTATTCTTACCGTCTTT 2-11-4 TTattcttaccgtCTTT 434_1 -19.99 51359 435 ATCTGATCTCACACAT 3-10-3 ATCtgatctcacaCAT 435_1 -19.62 51438 436 CATCTGATCTCACACAT 4-11-2 CATCtgatctcacacAT 436_1 -20.82 51438 437 ACTTCCAGATTTCTACA 2-11-4 ACttccagatttcTACA 437_1 -21.44 51953 438 TTTATGTTTACTTCAT 3-10-3 TTTatgtttacttCAT 438_1 -16.05 52150 439 TAAAGATCCCATCACTC 3-11-3 TAAagatcccatcaCTC 439_1 -20.31 52549 440 TAAAGATCCCATCACT 4-10-2 TAAAgatcccatcaCT 440_1 -18.82 52550 441 CCTAAAGATCCCATCAC 2-12-3 CCtaaagatcccatCAC 441_1 -22.32 52551 442 ATCATCAGTTACATCA 4-10-2 ATCAtcagttacatCA 442_1 -18.64 52579 443 ACTCTCACTGTAACTTT 4-11-2 ACTCtcactgtaactTT 443_ -19.76 53012 444 AACTCTCACTGTAACTT 3-11-3 AACtctcactgtaaCTT 444_1 -18.53 53013 445 ACTCTCACTGTAACTT 3-10-3 ACTctcactgtaaCTT 445_1 -19.04 53013 446 AACTCTCACTGTAACT 4-10-2 AACTctcactgtaaCT 446_1 -17.97 53014 447 CAACTCTCACTGTAACT 4-11-2 CAACtctcactgtaaCT 447_1 -20.01 53014 448 CCTTTCATTAACATTTA 3-11-3 CCTttcattaacatTTA 448_1 -19.03 54198 449 TTCCTTTCATTAACATTT 4-12-2 TTCCtttcattaacatTT 449_1 -19.92 54199 450 TAATCCTATTCCAACT 3-10-3 TAAtcctattccaACT 450_1 -18.05 54232 451 CTAATCCTATTCCAAC 2-10-4 CTaatcctattcCAAC 451_1 -18.65 54233 452 CTCTAATCCTATTCCA 3-10-3 CTCtaatcctattCCA 452_1 -22.58 54235 453 TCTCTAATCCTATTCC 4-10-2 TCTCtaatcctattCC 453_1 -21.78 54236 454 TTGTCTCTAATCCTATT 2-11-4 TTgtctctaatccTATT 454_1 -19.70 54238 455 TTGTCTCTAATCCTAT 2-10-4 TTgtctctaatcCTAT 455_1 -19.45 54239 456 TCTTTAAGCTTCCCAC 2-10-4 TCtttaagcttcCCAC 456_1 -22.96 54609 457 AAACTACCCTGCACAA 3-10-3 AAActaccctgcaCAA 457_1 -18.41 54924 458 CCATGCTACATAAACC 4-10-2 CCATgctacataaaCC 458_1 -22.25 55337 459 TCCATGCTACATAAAC 4-10-2 TCCAtgctacataaAC 459_1 -18.64 55338 460 ACTCCTAAGAATTACA 4-10-2 ACTCctaagaattaCA 460_1 -17.62 59565 461 GAAACTATTACTCCTA 2-10-4 GAaactattactCCTA 461_1 -19.06 59574 462 TGAAACTATTACTCCT 3-10-3 TGAaactattactCCT 462_1 -19.30 59575 463 ATGAAACTATTACTCC 2-10-4 ATgaaactattaCTCC 463_1 -17.96 59576 464 AACAACTCATGCCACA 2-10-4 AAcaactcatgcCACA 464_1 -19.72 60012 465 AAATATTGCCACCATT 2-10-4 AAatattgccacCATT 465_1 -17.78 60298 466 GTTACATATTCTTTCAC 3-11-3 GTTacatattctttCAC 466_1 -18.76 60448 467 TCATACTTGCTTTAAT 4-10-2 TCATacttgctttaAT 467_1 -17.29 60821 468 ATCCTGATAATTAACT 4-10-2 ATCCtgataattaaCT 468_1 -17.73 61925 469 CCTTAATCTGTATCAC 3-10-3 CCTtaatctgtatCAC 469_1 -19.92 62287 470 ATACACAGCACATATT 2-10-4 ATacacagcacaTATT 470_1 -17.58 62422 471 TCAGAATAATTCTCCT 3-10-3 TCAgaataattctCCT 471_1 -19.81 62443 472 TCTTCAGCTTTCTAAAT 4-11-2 TCTTcagctttctaaAT 472_1 -18.58 64113 473 AGTCCTTCCTTTAACCA 2-13-2 AGtccttcctttaacCA 473_1 -22.20 64461 474 TAGTCCTTCCTTTAACC 2-13-2 TAgtccttcctttaaCC 474_1 -22.12 64462 475 TTTAACCTTGCTTATA 2-10-4 TTtaaccttgctTATA 475_1 -17.50 65272 476 ATCCCTTTGTAATCAT 4-10-2 ATCCctttgtaatcAT 476_1 -20.31 66840 477 CTTGCATTTCTAATTAC 3-11-3 CTTgcatttctaatTAC 477_1 -18.09 67426 478 CTTGTCAAATCATTTCT 4-11-2 CTTGtcaaatcatttCT 478_1 -19.10 68194 479 CCATCTAATGATTATT 4-10-2 CCATctaatgattaTT 479_1 -17.28 68328 480 TATCAGTTATCCAATA 4-10-2 TATCagttatccaaTA 480_1 -17.39 68805 481 TCACTGCCATCAATAC 4-10-2 TCACtgccatcaatAC 481_1 -19.71 68921 482 TGTCATCTACAAATCA 4-10-2 TGTCatctacaaatCA 482_1 -18.01 70133 483 CTCTTTAGATTCATCC 4-10-2 CTCTttagattcatCC 483_1 -20.94 72377 484 ACTCTTTAGATTCATC 2-10-4 ACtctttagattCATC 484_1 -17.81 72378 485 CAACTCTATGACTACC 2-10-4 CAactctatgacTACC 485_1 -20.07 72826 486 ACCTGTAATACTTCTT 4-10-2 ACCTgtaatacttcTT 486_1 -19.67 72861 487 GAATTCTTTATTCCTCC 2-11-4 GAattctttattcCTCC 487_1 -22.53 72887 488 ATCTGAATCAAACCTT 2-10-4 ATctgaatcaaaCCTT 488_1 -17.97 73474 489 ACTTTACTGCCATAATC 3-11-3 ACTttactgccataATC 489_1 -19.60 73992 490 TTACTCTTAGCAACCT 4-10-2 TTACtcttagcaacCT 490_1 -20.19 74791 491 CACCAGTATTTCTTCTT 4-11-2 CACCagtatttcttcTT 491_1 -22.15 74851 492 TTCACCAGTATTTCTTC 4-11-2 TTCAccagtatttctTC 492_1 -20.43 74853 493 CCAAATAAGCAAACTC 3-10-3 CCAaataagcaaaCTC 493_1 -17.54 75840 494 CCCAAATAAGCAAACT 4-10-2 CCCAaataagcaaaCT 494_1 -20.23 75841 495 GACTACATTCTCAATA 3-10-3 GACtacattctcaATA 495_1 -17.49 76238 496 TTGTCAATCTTTATTCT 4-11-2 TTGTcaatctttattCT 496_1 -18.85 76254 497 AGCTTACCAAATATTC 4-10-2 AGCTtaccaaatatTC 497_1 -18.68 76811 498 TTACACATGTATATCC 3-10-3 TTAcacatgtataTCC 498_1 -18.23 77114 499 ATCCTGTTAATACCAT 2-10-4 ATcctgttaataCCAT 499_1 -20.41 80468 500 TTCTTAGTCACACACA 4-10-2 TTCTtagtcacacaCA 500_1 -19.37 81047 501 TTCTGTTTCCATTTACA 4-11-2 TTCTgtttccatttaCA 501_1 -21.31 82233 502 TCTATATCAAGTTCCTT 2-11-4 TCtatatcaagttCCTT 502_1 -20.95 84166 503 ATTCAGTTACCAACTA 3-10-3 ATTcagttaccaaCTA 503_1 -18.37 85392 504 GCTTCTACTTAAATAT 3-10-3 GCTtctacttaaaTAT 504_1 -17.58 86974 505 CCCTCAAAGTAATTTC 4-10-2 CCCTcaaagtaattTC 505_1 -20.53 87728 506 AACATGTAATTTCCAT 2-10-4 AAcatgtaatttCCAT 506_1 -17.21 87810 507 CCAGACTCCAATATTT 4-10-2 CCAGactccaatatTT 507_1 -20.78 88417 508 CTTAGACTTCACCTTTC 2-11-4 CTtagacttcaccTTTC 508_1 -20.56 88991 509 CTGCTTAATTATATCA 4-10-2 CTGCttaattatatCA 509_1 -18.85 90228 510 AAATTGTCTACCTTCCT 2-12-3 AAattgtctaccttCCT 510_1 -20.62 90474 511 CACTTAGAATATCCCT 2-10-4 CActtagaatatCCCT 511_1 -22.28 91625 512 ATCCAAAGTTTCTTTC 4-10-2 ATCCaaagtttcttTC 512_1 -18.64 91885 513 ATATTTGTCACCTAAC 4-10-2 ATATttgtcacctaAC 513_1 -17.12 92976 514 CTATTCTCAGTATTAT 3-10-3 CTAttctcagtatTAT 514_1 -17.42 94304 515 CCATTCAATGATCACT 2-10-4 CCattcaatgatCACT 515_1 -20.55 94528 516 CACTAGTACTCTTATT 4-10-2 CACTagtactcttaTT 516_1 -18.01 95653 517 GCCACAACATCTATTT 4-10-2 GCCAcaacatctatTT 517_1 -21.53 96751 518 AGCACATATACCATCA 4-10-2 AGCAcatataccatCA 518_1 -21.98 97636 519 GTCATCTAACTTCTTAC 3-11-3 GTCatctaacttctTAC 519_1 -19.25 98480 520 TGTCATCTAACTTCTTA 4-11-2 TGTCatctaacttctTA 520_1 -19.69 98481 521 CCCTTATAGTTATTAA 3-10-3 CCCttatagttatTAA 521_1 -19.32 99646 522 TCCATAGAATTCTTCA 4-10-2 TCCAtagaattcttCA 522_1 -19.92 100334 523 TTGATTCCACCATTAA 3-10-3 TTGattccaccatTAA 523_1 -18.05 101110 524 CAGCCATAAACTATAT 4-10-2 CAGCcataaactatAT 524_1 -18.60 101898 525 TATGACTTATTCCATA 2-10-4 TAtgacttattcCATA 525_1 -17.88 102558 526 GTTAACCTATATTTCA 4-10-2 GTTAacctatatttCA 526_1 -17.69 103589 527 TGTCTATTCTCTTCATT 4-11-2 TGTCtattctcttcaTT 527_1 -20.62 104309 528 TTACTCTTTGATTTCAT 3-11-3 TTActctttgatttCAT 528_1 -18.39 105686 529 GATAATTCCAAATCCC 2-10-4 GAtaattccaaaTCCC 529_1 -20.99 107972 530 TCTTATCCTTGAATTTC 4-11-2 TCTTatccttgaattTC 530_1 -18.85 108257 531 ATATCCCTTGATTATCC 3-11-3 ATAtcccttgattaTCC 531_1 -22.75 109407 532 TTAGTATACCCTTTAT 3-10-3 TTAgtatacccttTAT 532_1 -18.67 110210 533 CTCTTTGTCAAATACT 4-10-2 CTCTttgtcaaataCT 533_1 -18.16 110768 534 CCAAACTGTCTTCTAAT 2-11-4 CCaaactgtcttcTAAT 534_1 -19.87 111811 535 TCCAAACTGTCTTCTAA 3-12-2 TCCaaactgtcttctAA 535_1 -18.33 111812 536 CCAGCATATTATATAC 3-10-3 CCAgcatattataTAC 536_1 -18.96 112149 537 TCCAGCATATTATATA 4-10-2 TCCAgcatattataTA 537_1 -19.41 112150 538 TCATTGAACAACTCTTC 4-11-2 TCATtgaacaactctTC 538_1 -18.01 112945 539 CTGCCATCTTTATTTAT 4-11-2 CTGCcatctttatttAT 539_1 -21.89 113533 540 TGAAACATTCTTCCCAC 2-12-3 TGaaacattcttccCAC 540_1 -19.76 114274 541 TTTATTAGATTACTCC 2-10-4 TTtattagattaCTCC 541_1 -17.38 114495 542 TTCCAGCTTATTTACCT 3-12-2 TTCcagcttatttacCT 542_1 -21.28 114831 543 AGCATCATATAAACCT 3-10-3 AGCatcatataaaCCT 543_1 -20.62 115355 544 GTACTTACACATCTAT 2-10-4 GTacttacacatCTAT 544_1 -18.96 116105 545 TGTACTTACACATCTA 3-10-3 TGTacttacacatCTA 545_1 -19.38 116106 546 ATTTCTCTATGTCACAT 3-11-3 ATTtctctatgtcaCAT 546_1 -19.28 117096 547 CAAACCTACGTCTCTC 2-10-4 CAaacctacgtcTCTC 547_1 -20.87 117189 548 GTATTTACTCTTTACCT 3-11-3 GTAtttactctttaCCT 548_1 -22.15 117476 549 CTAATGCAATAACCCA 2-10-4 CTaatgcaataaCCCA 549_1 -21.79 118293 550 ACTAATGCAATAACCC 3-10-3 ACTaatgcaataaCCC 550_1 -20.53 118294 551 AGCTCTAAACCTTCAA 3-10-3 AGCtctaaaccttCAA 551_1 -20.51 118756 552 TATTTGTCACCAAACC 3-10-3 TATttgtcaccaaACC 552_1 -19.63 119621 553 CTCAGACATCTCAATA 4-10-2 CTCAgacatctcaaTA 553_1 -19.25 120655 554 TCTCAGCTTCTTCAAAT 2-12-3 TCtcagcttcttcaAAT 554_1 -18.33 123733 555 GCCAATACCCACAAAC 3-10-3 GCCaatacccacaAAC 555_1 -22.03 124163 556 CCTCTGACAACCATTA 4-10-2 CCTCtgacaaccatTA 556_1 -22.57 125512 557 CAGATAACTCTAAACC 4-10-2 CAGAtaactctaaaCC 557_1 -18.43 126882 558 CTAACTGTTTCTCAATT 3-11-3 CTAactgtttctcaATT 558_1 -18.10 127105 559 CCAAGATAATCATCAT 3-10-3 CCAagataatcatCAT 559_1 -18.37 127809 560 TACATATTGTACTTCT 4-10-2 TACAtattgtacttCT 560_1 -17.48 129020 561 TAGCCTACTTTAATAT 4-10-2 TAGCctactttaatAT 561_1 -18.67 129205 562 CATTTACAAGCACATA 2-10-4 CAtttacaagcaCATA 562_1 -17.81 129928 563 TTATTCTGACACACTT 3-10-3 TTAttctgacacaCTT 563_1 -17.49 130020 564 TACATTGACACCTAAT 4-10-2 TACAttgacacctaAT 564_1 -17.37 130884 565 TTTACATTGACACCTA 2-10-4 TTtacattgacaCCTA 565_1 -19.42 130886 566 TGTATATAACTATTCC 4-10-2 TGTAtataactattCC 566_1 -17.79 131404 567 GAATCTTCTAATTCCAC 2-11-4 GAatcttctaattCCAC 567_1 -20.40 132514 568 TGCTCACTAACTACAC 3-10-3 TGCtcactaactaCAC 568_1 -20.66 133367 569 TGCTACCATCATTACCT 2-13-2 TGctaccatcattacCT 569_1 -21.32 136198 570 TTTATCAATATCTTCTCACT 1-13- TttatcaatatcttCtCaCT 570_1 -19.69 5784 1-1-1- 1-2 570 TTTATCAATATCTTCTCACT 1-2-1- TttAtcaatatcttCtcACT 570_2 -19.67 5784 10-1-2- 3 570 TTTATCAATATCTTCTCACT 1-5-1- TttatcAatatcttCtcACT 570_3 -19.65 5784 7-1-2-3 570 TTTATCAATATCTTCTCACT 1-1-1- TtTatcaatatcttCtcaCT 570_4 -19.75 5784 11-1-3- 2 570 TTTATCAATATCTTCTCACT 1-2-1- TttAtcAatatcttctcaCT 570_5 -18.21 5784 2-1-11- 2 570 TTTATCAATATCTTCTCACT 1-4-1- TttatCaatatcttCtcaCT 570_6 -19.69 5784 8-1-3-2 570 TTTATCAATATCTTCTCACT 1-2-1- TttAtcAatatcttctCaCT 570_7 -18.88 5784 2-1-9- 1-1-2 570 TTTATCAATATCTTCTCACT 1-2-1- TttAtCaatatcttctcACT 570_8 -19.36 5784 1-1-11- 3 570 TTTATCAATATCTTCTCACT 1-4-1- TttatCaatatcttctCaCT 570_9 -19.38 5784 10-1-1- 2 570 TTTATCAATATCTTCTCACT 2-1-1- TTtAtcaatatcttCtCaCT 570_10 -20.60 5784 10-1-1- 1-1-2 570 TTTATCAATATCTTCTCACT 1-4-1- TttatCaatatcttCtCaCT 570_11 -20.36 5784 8-1-1- 1-1-2 570 TTTATCAATATCTTCTCACT 1-2-1- TttAtCaatatcttCtcACT 570_12 -20.34 5784 1-1-8- 1-2-3 570 TTTATCAATATCTTCTCACT 1-2-1- TttAtcAatatcttCtcaCT 570_13 -19.19 5784 2-1-7- 1-3-2 570 TTTATCAATATCTTCTCACT 1-1-2- TtTAtCaatatcttctCaCT 570_14 -21.24 5784 1-1-10- 1-1-2 571 TTTATCAATATCTTCTCAC 1-12- TttatcaatatctTCtCAC 571_1 -19.16 5785 2-1-3 571 TTTATCAATATCTTCTCAC 2-1-1- TTtAtCaatatcTTctCAC 571_2 -20.17 5785 1-1-6- 2-2-3 571 TTTATCAATATCTTCTCAC 3-2-1- TTTatCaatatctTCtcAC 571_3 -19.79 5785 7-2-2-2 571 TTTATCAATATCTTCTCAC 1-2-3- TttATCaatatcttCtcAC 571_4 -18.78 5785 8-1-2-2 571 TTTATCAATATCTTCTCAC 1-4-1- TttatCaatatcttcTCAC 571_5 -19.06 5785 9-4 571 TTTATCAATATCTTCTCAC 2-1-1- TTtAtCaatatcttCtCAC 571_6 -19.75 5785 1-1-8- 1-1-3 571 TTTATCAATATCTTCTCAC 1-1-1- TtTatCaatatcTtctCAC 571_7 -19.11 5785 2-1-6- 1-3-3 571 TTTATCAATATCTTCTCAC 2-1-3- TTtATCaatatcTtctcAC 571_8 -19.13 5785 6-1-4-2 571 TTTATCAATATCTTCTCAC 4-12-3 TTTAtcaatatcttctCAC 571_9 -20.38 5785 571 TTTATCAATATCTTCTCAC 1-1-2- TtTAtCaatatcTtctCAC 571_10 -20.24 5785 1-1-6- 1-3-3 571 TTTATCAATATCTTCTCAC 2-1-1- TTtAtCaatatctTCtcAC 571_11 -18.65 5785 1-1-7- 2-2-2 571 TTTATCAATATCTTCTCAC 3-2-1- TTTatCaatatcttCtCAC 571_12 -20.89 5785 8-1-1-3 571 TTTATCAATATCTTCTCAC 1-3-2- TttaTCaatatcttCtCAC 571_13 -19.96 5785 8-1-1-3 571 TTTATCAATATCTTCTCAC 1-2-1- TttAtCaatatcttcTCAC 571_14 -19.16 5785 1-1-9-4 572 TTTATCAATATCTTCTCA 2-1-1- TTtAtCaatatctTCtCA 572_1 -18.69 5786 1-1-7- 2-1-2 572 TTTATCAATATCTTCTCA 3-2-1- TTTatCaatatcTtCtCA 572_2 -19.36 5786 6-1-1- 1-1-2 572 TTTATCAATATCTTCTCA 1-4-1- TttatCaatatcTtCTCA 572_3 -19.19 5786 6-1-1-4 572 TTTATCAATATCTTCTCA 1-2-3- TttATCaatatcTtcTCA 572_4 -19.56 5786 6-1-2-3 572 TTTATCAATATCTTCTCA 4-1-1- TTTAtCaatatctTctCA 572_5 -19.37 5786 7-1-2-2 572 TTTATCAATATCTTCTCA 1-2-3- TttATCaatatcttCtCA 572_6 -18.83 5786 8-1-1-2 572 TTTATCAATATCTTCTCA 3-2-1- TTTatCaatatcttcTCA 572_7 -19.07 5786 9-3 572 TTTATCAATATCTTCTCA 1-2-1- TttAtcaatatcttCTCA 572_8 -18.10 5786 10-4 572 TTTATCAATATCTTCTCA 4-10- TTTAtcaatatcttCtCA 572_9 -19.31 5786 1-1-2 572 TTTATCAATATCTTCTCA 2-1-3- TTtATCaatatcTtCtCA 572_10 -20.15 5786 6-1-1- 1-1-2 572 TTTATCAATATCTTCTCA 3-2-1- TTTatCaatatcTtcTCA 572_11 -19.59 5786 6-1-2-3 572 TTTATCAATATCTTCTCA 1-1-2- TtTAtCaatatctTCtCA 572_12 -19.64 5786 1-1-7- 2-1-2 572 TTTATCAATATCTTCTCA 4-9-1- TTTAtcaatatctTcTCA 572_13 -19.90 5786 1-3 572 TTTATCAATATCTTCTCA 1-3-2- TttaTCaatatcttCTCA 572_14 -19.80 5786 8-4 573 TATACCTTTCTTTAACCCTT 1-4-1- TatacCtttctttaacCcTT 573_1 -22.72 8116 10-1-1- 2 573 TATACCTTTCTTTAACCCTT 2-4-1- TAtaccTttctttaacccTT 573_2 -22.80 8116 11-2 573 TATACCTTTCTTTAACCCTT 1-3-1- TataCctttctttaaCccTT 573_3 -22.72 8116 10-1-2- 2 573 TATACCTTTCTTTAACCCTT 1-4-1- TatacCtttctttaaCccTT 573_4 -22.82 8116 9-1-2-2 573 TATACCTTTCTTTAACCCTT 1-5-1- TataccTttctttaacCcTT 573_5 -22.35 8116 9-1-1-2 573 TATACCTTTCTTTAACCCTT 1-15- TatacctttctttaacCcTT 573_6 -21.83 8116 1-1-2 573 TATACCTTTCTTTAACCCTT 1-2-1- TatAcCtttctttaacCcTT 573_7 -22.91 8116 1-1-10- 1-1-2 573 TATACCTTTCTTTAACCCTT 2-2-1- TAtaCcTttctttaacccTT 573_8 -23.58 8116 1-1-11- 2 573 TATACCTTTCTTTAACCCTT 2-3-1- TAtacCtttctttaacccTT 573_9 -23.17 8116 12-2 573 TATACCTTTCTTTAACCCTT 1-3-1- TataCctttctttAAcCcTT 573_10 -23.35 8116 8-2-1- 1-1-2 573 TATACCTTTCTTTAACCCTT 2-2-1- TAtaCcTttctttaAcCcTT 573_11 -24.68 8116 1-1-7- 1-1-1- 1-2 573 TATACCTTTCTTTAACCCTT 2-4-1- TAtaccTttctttaaCCcTT 573_12 -25.86 8116 8-2-1-2 573 TATACCTTTCTTTAACCCTT 2-3-1- TAtacCtttctttaaCccTT 573_13 -23.96 8116 9-1-2-2 573 TATACCTTTCTTTAACCCTT 2-3-1- TAtacCtttctttaacCcTT 573_14 -23.85 8116 10-1-1- 2 574 TTATACCTTTCTTTAACCCT 1-1-1- TtAtacctttcttTaaccCT 574_1 -22.31 8117 10-1-4- 2 574 TTATACCTTTCTTTAACCCT 1-13- TtatacctttctttAaCcCT 574_2 -22.38 8117 1-1-1- 1-2 574 TTATACCTTTCTTTAACCCT 1-1-1- TtAtacCtttctttaaccCT 574_3 -22.47 8117 3-1-11- 2 574 TTATACCTTTCTTTAACCCT 1-3-1- TtatAcCtttctttAaccCT 574_4 -22.68 8117 1-1-7- 1-3-2 574 TTATACCTTTCTTTAACCCT 1-4-1- TtataCctttctttAaccCT 574_5 -22.38 8117 8-1-3-2 574 TTATACCTTTCTTTAACCCT 1-1-1- TtAtacctttctttaaCcCT 574_6 -22.36 8117 13-1-1- 2 574 TTATACCTTTCTTTAACCCT 1-3-1- TtatAcctttctttaaCcCT 574_7 -22.46 8117 11-1-1- 2 574 TTATACCTTTCTTTAACCCT 1-1-1- TtAtaCctttctttaaccCT 574_8 -22.36 8117 2-1-12- 2 574 TTATACCTTTCTTTAACCCT 1-5-1- TtatacCtttctttaaccCT 574_9 -22.37 8117 11-2 574 TTATACCTTTCTTTAACCCT 1-1-1- TtAtaCctttctttaaCcCT 574_10 -23.14 8117 2-1-10- 1-1-2 574 TTATACCTTTCTTTAACCCT 1-1-1- TtAtacCtttctttaaCcCT 574_11 -23.25 8117 3-1-9- 1-1-2 574 TTATACCTTTCTTTAACCCT 1-1-1- TtAtacCtttctttaacCCT 574_12 -24.75 8117 3-1-10- 3 574 TTATACCTTTCTTTAACCCT 1-1-1- TtAtaCCtttctttaaccCT 574_13 -24.85 8117 2-2-11- 2 574 TTATACCTTTCTTTAACCCT 1-3-1- TtatAcCtttctttaaccCT 574_14 -22.56 8117 1-1-11- 2 575 TTTATACCTTTCTTTAACCC 1-2-1- TttAtacctttctTtaacCC 575_1 -21.69 8118 9-1-4-2 575 TTTATACCTTTCTTTAACCC 1-12- TttatacctttctTtaacCC 575_2 -21.59 8118 1-4-2 575 TTTATACCTTTCTTTAACCC 1-12- TttatacctttctTtAacCC 575_3 -21.71 8118 1-1-1- 2-2 575 TTTATACCTTTCTTTAACCC 1-4-1- TttatAcctttctttaAcCC 575_4 -21.90 8118 10-1-1- 2 575 TTTATACCTTTCTTTAACCC 1-13- TttatacctttcttTaacCC 575_5 -22.01 8118 1-3-2 575 TTTATACCTTTCTTTAACCC 2-1-1- TTtAtacctttctttaacCC 575_6 -22.20 8118 14-2 575 TTTATACCTTTCTTTAACCC 1-14- TttatacctttctttAAcCC 575_7 -22.02 8118 2-1-2 575 TTTATACCTTTCTTTAACCC 1-14- TttatacctttctttAacCC 575_8 -21.41 8118 1-2-2 575 TTTATACCTTTCTTTAACCC 1-15- TttatacctttctttaAcCC 575_9 -21.71 8118 1-1-2 575 TTTATACCTTTCTTTAACCC 2-1-1- TTtAtacctttctTtaacCC 575_10 -22.50 8118 9-1-4-2 575 TTTATACCTTTCTTTAACCC 1-2-1- TttAtacctttcttTaacCC 575_11 -22.11 8118 10-1-3- 2 575 TTTATACCTTTCTTTAACCC 1-4-2- TttatACctttctttAAcCC 575_12 -23.40 8118 8-2-1-2 575 TTTATACCTTTCTTTAACCC 1-2-1- TttAtaCctttctttaAcCC 575_13 -22.59 8118 2-1-9- 1-1-2 575 TTTATACCTTTCTTTAACCC 1-1-2- TtTAtacctttctttaacCC 575_14 -23.15 8118 14-2 576 TTTTATACCTTTCTTTAACC 1-1-1- TtTtatacctttcTTtaaCC 576_1 -21.12 8119 10-2-3- 2 576 TTTTATACCTTTCTTTAACC 1-3-1- TtttAtacctttcTttaaCC 576_2 -20.10 8119 8-1-4-2 576 TTTTATACCTTTCTTTAACC 1-1-1- TtTtatacctttcTttAACC 576_3 -21.45 8119 10-1-2- 4 576 TTTTATACCTTTCTTTAACC 3-11- TTTtatacctttctTtAaCC 576_4 -21.54 8119 1-1-1- 1-2 576 TTTTATACCTTTCTTTAACC 2-4-1- TTttatAcctttctTtaaCC 576_5 -20.80 8119 7-1-3-2 576 TTTTATACCTTTCTTTAACC 1-14- TtttatacctttcttTaaCC 576_6 -20.22 8119 1-2-2 576 TTTTATACCTTTCTTTAACC 1-15- TtttatacctttctttAaCC 576_7 -19.61 8119 1-1-2 576 TTTTATACCTTTCTTTAACC 1-5-1- TtttatAcctttctttaACC 576_8 -20.51 8119 10-3 576 TTTTATACCTTTCTTTAACC 1-1-2- TtTTatacctttctttaaCC 576_9 -21.03 8119 14-2 576 TTTTATACCTTTCTTTAACC 1-1-2- TtTTatacctttctTtAaCC 576_10 -21.46 8119 10-1-1- 1-1-2 576 TTTTATACCTTTCTTTAACC 2-2-1- TTttAtacctttctTtaaCC 576_11 -20.70 8119 9-1-3-2 576 TTTTATACCTTTCTTTAACC 1-5-1- TtttatAcctttctTtaaCC 576_12 -19.99 8119 7-1-3-2 576 TTTTATACCTTTCTTTAACC 1-1-1- TtTtatacctttcttTAaCC 576_13 -21.68 8119 12-2-1- 2 576 TTTTATACCTTTCTTTAACC 1-1-1- TtTtAtacctttctttaaCC 576_14 -19.89 8119 1-1-13- 2 577 TTTTTATACCTTTCTTTAAC 1-12- TttttatacctttCttTAAC 577_1 -19.19 8120 1-2-4 577 TTTTTATACCTTTCTTTAAC 1-2-1- TttTtatacctttCtTTaAC 577_2 -18.96 8120 9-1-1- 2-1-2 577 TTTTTATACCTTTCTTTAAC 2-12- TTtttatacctttcTTTaAC 577_3 -19.52 8120 3-1-2 577 TTTTTATACCTTTCTTTAAC 1-1-1- TtTttAtacctttCTttaAC 577_4 -18.71 8120 2-1-7- 2-3-2 577 TTTTTATACCTTTCTTTAAC 4-9-1- TTTTtatacctttCtTtaAC 577_5 -19.85 8120 1-1-2-2 577 TTTTTATACCTTTCTTTAAC 3-1-1- TTTtTatacctttCtTtAAC 577_6 -20.08 8120 8-1-1- 1-1-3 577 TTTTTATACCTTTCTTTAAC 2-1-2- TTtTTatacctttCTttAAC 577_7 -20.97 8120 8-2-2-3 577 TTTTTATACCTTTCTTTAAC 1-1-2- TtTTtatacctttcTTtAAC 577_8 -18.89 8120 10-2-1- 3 577 TTTTTATACCTTTCTTTAAC 1-3-2- TtttTAtacctttCtttaAC 577_9 -18.97 8120 7-1-4-2 577 TTTTTATACCTTTCTTTAAC 1-2-1- TttTtatacctttCTtTaAC 577_10 -19.34 8120 9-2-1- 1-1-2 577 TTTTTATACCTTTCTTTAAC 2-3-1- TTtttAtacctttCTttAAC 577_11 -19.53 8120 7-2-2-3 577 TTTTTATACCTTTCTTTAAC 1-1-2- TtTTtatacctttCtTtAAC 577_12 -18.84 8120 9-1-1- 1-1-3 577 TTTTTATACCTTTCTTTAAC 1-3-2- TtttTAtacctttCtTtaAC 577_13 -19.27 8120 7-1-1- 1-2-2 577 TTTTTATACCTTTCTTTAAC 3-1-1- TTTtTatacctttCttTaAC 577_14 -20.20 8120 8-1-2- 1-1-2 578 TTTTTTCTTACTATCTTCAA 1-5-1- TtttttCttactatCTtcAA 578_1 -19.02 8584 7-2-2-2 578 TTTTTTCTTACTATCTTCAA 2-2-1- TTttTtCttactatCtTcAA 578_2 -19.31 8584 1-1-7- 1-1-1- 1-2 578 TTTTTTCTTACTATCTTCAA 1-2-2- TttTTtcttactatCttCAA 578_3 -20.05 8584 9-1-2-3 578 TTTTTTCTTACTATCTTCAA 1-1-1- TtTtTtCttactatCttcAA 578_4 -18.43 8584 1-1-1- 1-7-1- 3-2 578 TTTTTTCTTACTATCTTCAA 3-3-1- TTTtttCttactatcTtcAA 578_5 -18.99 8584 8-1-2-2 578 TTTTTTCTTACTATCTTCAA 2-1-2- TTtTTtCttactatcTtcAA 578_6 -19.29 8584 1-1-8- 1-2-2 578 TTTTTTCTTACTATCTTCAA 1-1-3- TtTTTtCttactatctTcAA 578_7 -19.15 8584 1-1-9- 1-1-2 578 TTTTTTCTTACTATCTTCAA 2-1-1- TTtTttcttactatcTtCAA 578_8 -19.58 8584 11-1-1- 3 578 TTTTTTCTTACTATCTTCAA 1-4-1- TttttTcttactatctTCAA 578_9 -19.31 8584 10-4 579 TTTTTTTCTTACTATCTTCA 1-12- TttttttcttactAtCttCA 579_1 -19.29 8585 1-1-1- 2-2 579 TTTTTTTCTTACTATCTTCA 2-1-1- TTtTtttcttactAtcttCA 579_2 -19.42 8585 9-1-4-2 579 TTTTTTTCTTACTATCTTCA 1-1-1- TtTttTtcttactAtcttCA 579_3 -18.91 8585 2-1-7- 1-4-2 579 TTTTTTTCTTACTATCTTCA 1-1-2- TtTTtttcttactAtcTtCA 579_4 -19.94 8585 9-1-2- 1-1-2 579 TTTTTTTCTTACTATCTTCA 1-3-2- TtttTTtcttactatcTtCA 579_5 -19.84 8585 10-1-1- 2 579 TTTTTTTCTTACTATCTTCA 2-3-1- TTtttTtcttactatcttCA 579_6 -19.33 8585 12-2 579 TTTTTTTCTTACTATCTTCA 3-15-2 TTTttttcttactatcttCA 579_7 -19.84 8585 579 TTTTTTTCTTACTATCTTCA 1-2-2- TttTTttcttactatcttCA 579_8 -19.33 8585 13-2 579 TTTTTTTCTTACTATCTTCA 1-14- TttttttcttactatCttCA 579_9 -19.19 8585 1-2-2 580 ATTTTTTTCTTACTATCTTC 1-4-1- AttttTttcttactAtCtTC 580_1 -18.09 8586 8-1-1- 1-1-2 580 ATTTTTTTCTTACTATCTTC 2-1-1- ATtTttttcttactAtcTTC 580_2 -19.39 8586 10-1-2- 3 580 ATTTTTTTCTTACTATCTTC 1-3-2- AtttTTttcttactAtcTTC 580_3 -18.95 8586 8-1-2-3 580 ATTTTTTTCTTACTATCTTC 1-5-1- AtttttTtcttacTatcTTC 580_4 -18.98 8586 6-1-3-3 580 ATTTTTTTCTTACTATCTTC 2-2-1- ATttTtTtcttactAtctTC 580_5 -18.66 8586 1-1-7- 1-3-2 580 ATTTTTTTCTTACTATCTTC 1-1-3- AtTTTtttcttacTatctTC 580_6 -19.58 8586 8-1-4-2 580 ATTTTTTTCTTACTATCTTC 2-1-1- ATtTttttcttactatCtTC 580_7 -19.24 8586 12-1-1- 2 580 ATTTTTTTCTTACTATCTTC 1-1-1- AtTttTttcttactatcTTC 580_8 -18.34 8586 2-1-11- 3 580 ATTTTTTTCTTACTATCTTC 1-1-2- AtTTtTTtcttactatctTC 580_9 -18.94 8586 1-2-11- 2 581 AATTTTTTTCTTACTATCTT 1-4-1- AatttTtttcttaCtAtCTT 581_1 -18.53 8587 7-1-1- 1-1-3 581 AATTTTTTTCTTACTATCTT 1-3-1- AattTtTttcttaCTatcTT 581_2 -18.69 8587 1-1-6- 2-3-2 581 AATTTTTTTCTTACTATCTT 1-1-2- AaTTtttttcttacTAtcTT 581_3 -18.80 8587 10-2-2- 2 581 AATTTTTTTCTTACTATCTT 2-1-1- AAtTtTtttcttacTatCTT 581_4 -19.20 8587 1-1-8- 1-2-3 581 AATTTTTTTCTTACTATCTT 4-2-1- AATTttTttcttacTatcTT 581_5 -19.30 8587 7-1-3-2 581 AATTTTTTTCTTACTATCTT 2-2-2- AAttTTtttcttaCtATcTT 581_6 -19.52 8587 7-1-1- 2-1-2 581 AATTTTTTTCTTACTATCTT 1-12- AatttttttcttaCtaTCTT 581_7 -19.25 8587 1-2-4 581 AATTTTTTTCTTACTATCTT 1-1-4- AaTTTTtttcttaCtatcTT 581_8 -19.35 8587 7-1-4-2 581 AATTTTTTTCTTACTATCTT 2-1-3- AAtTTTtttcttactAtCTT 581_9 -19.68 8587 9-1-1-3 582 GTTTATACCCTTTCCAAT 1-1-1- GtTtAtacccttTCcaAT 582_1 -21.48 9209 1-1-7- 2-2-2 582 GTTTATACCCTTTCCAAT 1-12- GtttataccctttCCaAT 582_2 -22.28 9209 2-1-2 582 GTTTATACCCTTTCCAAT 1-3-1- GtttAtaccctttCcAAT 582_3 -20.46 9209 8-1-1-3 582 GTTTATACCCTTTCCAAT 1-1-1- GtTtAtaccctttcCaAT 582_4 -20.30 9209 1-1-9- 1-1-2 582 GTTTATACCCTTTCCAAT 2-11- GTttataccctttCcaAT 582_5 -21.64 9209 1-2-2 582 GTTTATACCCTTTCCAAT 1-1-2- GtTTataccctttCcAAT 582_6 -21.90 9209 9-1-1-3 582 GTTTATACCCTTTCCAAT 1-1-1- GtTtataccctttccaAT 582_7 -19.63 9209 13-2 582 GTTTATACCCTTTCCAAT 1-2-1- GttTataccctttccaAT 582_8 -20.05 9209 12-2 582 GTTTATACCCTTTCCAAT 1-13-4 GtttataccctttcCAAT 582_9 -21.59 9209 583 TGTTTATACCCTTTCCAA 2-1-1- TGtTtataccctttCcAA 583_1 -21.08 9210 10-1-1- 2 583 TGTTTATACCCTTTCCAA 1-4-1- TgtttAtaccctTtCcAA 583_2 -19.97 9210 6-1-1- 1-1-2 583 TGTTTATACCCTTTCCAA 1-3-1- TgttTataccctttCcAA 583_3 -20.30 9210 9-1-1-2 583 TGTTTATACCCTTTCCAA 2-1-1- TGtTtAtaccctTtccAA 583_4 -20.71 9210 1-1-6- 1-3-2 583 TGTTTATACCCTTTCCAA 1-2-1- TgtTtataccctTtcCAA 583_5 -21.40 9210 8-1-2-3 583 TGTTTATACCCTTTCCAA 1-4-1- TgtttAtaccctttcCAA 583_6 -20.89 9210 9-3 583 TGTTTATACCCTTTCCAA 1-1-2- TgTTtataccctttccAA 583_7 -20.27 9210 12-2 583 TGTTTATACCCTTTCCAA 1-12- TgtttatacccttTCcAA 583_8 -20.56 9210 2-1-2 583 TGTTTATACCCTTTCCAA 2-2-1- TGttTataccctttccAA 583_9 -20.74 9210 11-2 584 CTGTTTATACCCTTTCCA 1-1-1- CtGtttataccctTtcCA 584_1 -22.45 9211 10-1-2- 2 584 CTGTTTATACCCTTTCCA 1-12- CtgtttataccctTtcCA 584_2 -22.14 9211 1-2-2 584 CTGTTTATACCCTTTCCA 1-1-1- CtGtTtataccctttcCA 584_3 -22.45 9211 1-1-11- 2 584 CTGTTTATACCCTTTCCA 1-1-1- CtGtttataccctttcCA 584_4 -22.15 9211 13-2 584 CTGTTTATACCCTTTCCA 1-2-1- CtgTttataccctttcCA 584_5 -22.50 9211 12-2 584 CTGTTTATACCCTTTCCA 1-3-1- CtgtTtataccctttcCA 584_6 -22.14 9211 11-2 584 CTGTTTATACCCTTTCCA 1-4-1- CtgttTataccctttcCA 584_7 -22.57 9211 10-2 584 CTGTTTATACCCTTTCCA 1-15-2 CtgtttataccctttcCA 584_8 -21.84 9211 585 AATTATTTATACACCATCAT 2-1-1- AAtTaTttatacacCATCAT 585_1 -20.76 11511 1-1-8- 3-1-2 585 AATTATTTATACACCATCAT 3-2-2- AATtaTTtatacaCcATcAT 585_2 -20.88 11511 6-1-1- 2-1-2 585 AATTATTTATACACCATCAT 1-4-1- AattaTttatacaCCaTcAT 585_3 -19.62 11511 7-2-1- 1-1-2 585 AATTATTTATACACCATCAT 1-3-1- AattAtTtatacaCcatCAT 585_4 -18.98 11511 1-1-6- 1-3-3 585 AATTATTTATACACCATCAT 1-2-3- AatTATttatacaCcAtcAT 585_5 -19.65 11511 7-1-1- 1-2-2 585 AATTATTTATACACCATCAT 1-1-2- AaTTatttatacaccAtCAT 585_6 -19.53 11511 11-1-1- 3 585 AATTATTTATACACCATCAT 2-2-1- AAttAtttatacacCaTCAT 585_7 -20.11 11511 9-1-1-4 585 AATTATTTATACACCATCAT 3-1-2- AATtATttatacacCatCAT 585_8 -21.48 11511 8-1-2-3 585 AATTATTTATACACCATCAT 4-2-1- AATTatTtatacacCatcAT 585_9 -19.60 11511 7-1-3-2 585 AATTATTTATACACCATCAT 2-1-1- AAtTatTtatacaCCAtcAT 585_10 -21.69 11511 2-1-6- 3-2-2 585 AATTATTTATACACCATCAT 1-3-2- AattATttatacaCcAtCAT 585_11 -19.97 11511 7-1-1- 1-1-3 585 AATTATTTATACACCATCAT 2-1-3- AAtTATttatacacCaTcAT 585_12 -20.42 11511 8-1-1- 1-1-2 585 AATTATTTATACACCATCAT 1-1-2- AaTTaTttatacacCatCAT 585_13 -20.49 11511 1-1-8- 1-2-3 585 AATTATTTATACACCATCAT 2-1-1- AAtTatTtatacaccaTCAT 585_14 -20.47 11511 2-1-9-4 586 AAATTATTTATACACCATCA 1-12- AaattatttatacACCaTCA 586_1 -20.58 11512 3-1-3 586 AAATTATTTATACACCATCA 1-1-1- AaAttAtttatacAcCAtCA 586_2 -18.56 11512 2-1-7- 1-1-2- 1-2 586 AAATTATTTATACACCATCA 3-2-2- AAAttATttatacACcatCA 586_3 -19.68 11512 6-2-3-2 586 AAATTATTTATACACCATCA 4-10- AAATtatttatacaCcaTCA 586_4 -20.15 11512 1-2-3 586 AAATTATTTATACACCATCA 1-1-4- AaATTAtttatacaCcAtCA 586_5 -20.72 11512 8-1-1- 1-1-2 586 AAATTATTTATACACCATCA 2-1-2- AAaTTaTttatacaCcatCA 586_6 -19.39 11512 1-1-7- 1-3-2 586 AAATTATTTATACACCATCA 1-3-2- AaatTAtttatacAcCaTCA 586_7 -19.65 11512 7-1-1- 1-1-3 586 AAATTATTTATACACCATCA 1-1-3- AaATTatttatacAccATCA 586_8 -20.88 11512 8-1-2-4 586 AAATTATTTATACACCATCA 2-2-1- AAatTaTttatacaccATCA 586_9 -19.63 11512 1-1-9-4 586 AAATTATTTATACACCATCA 1-1-1- AaAtTaTttatacACCatCA 586_10 -20.95 11512 1-1-1- 1-6-3- 2-2 586 AAATTATTTATACACCATCA 1-3-2- AaatTAtttatacAcCAtCA 586_11 -20.00 11512 7-1-1- 2-1-2 586 AAATTATTTATACACCATCA 2-1-2- AAaTTaTttatacaCcAtCA 586_12 -19.44 11512 1-1-7- 1-1-1- 1-2 586 AAATTATTTATACACCATCA 3-2-1- AAAttAtttatacaCcaTCA 586_13 -19.00 11512 8-1-2-3 586 AAATTATTTATACACCATCA 1-1-4- AaATTAtttatacacCaTCA 586_14 -21.59 11512 9-1-1-3 587 AAAATTATTTATACACCATC 2-3-1- AAaatTatttataCaCCATC 587_1 -21.17 11513 7-1-1-5 587 AAAATTATTTATACACCATC 1-2-2- AaaATtatttatacACCATC 587_2 -21.34 11513 9-6 587 AAAATTATTTATACACCATC 2-3-2- AAaatTAtttataCACcATC 587_3 -20.67 11513 6-3-1-3 587 AAAATTATTTATACACCATC 3-1-1- AAAaTtAtttatacACCaTC 587_4 -19.11 11513 1-1-7- 3-1-2 587 AAAATTATTTATACACCATC 7-6-1- AAAATTAtttataCaCcaTC 587_5 -20.66 11513 1-1-2-2 587 AAAATTATTTATACACCATC 1-1-1- AaAaTTatttatacACcATC 587_6 -18.20 11513 1-2-8- 2-1-3 587 AAAATTATTTATACACCATC 1-1-5- AaAATTAtttataCAccaTC 587_7 -20.71 11513 6-2-3-2 587 AAAATTATTTATACACCATC 2-1-3- AAaATTatttataCacCATC 587_8 -20.87 11513 7-1-2-4 587 AAAATTATTTATACACCATC 4-1-1- AAAAtTatttatacAcCATC 587_9 -19.30 11513 8-1-1-4 587 AAAATTATTTATACACCATC 1-1-2- AaAAtTAtttataCACcaTC 587_10 -20.13 11513 1-2-6- 3-2-2 587 AAAATTATTTATACACCATC 1-2-3- AaaATTatttataCaCCaTC 587_11 -20.44 11513 7-1-1- 2-1-2 587 AAAATTATTTATACACCATC 3-1-2- AAAaTTatttataCacCATC 587_12 -20.27 11513 7-1-2-4 587 AAAATTATTTATACACCATC 3-2-1- AAAatTatttatacACCaTC 587_13 -19.30 11513 8-3-1-2 587 AAAATTATTTATACACCATC 2-1-3- AAaATTatttatacACcATC 587_14 -19.52 11513 8-2-1-3 588 TAAAATTATTTATACACCAT 2-3-1- TAaaaTtatttatAcACCAT 588_1 -20.14 11514 7-1-1-5 588 TAAAATTATTTATACACCAT 1-2-1- TaaAatTatttatACaCCAT 588_2 -20.15 11514 2-1-6- 2-1-4 588 TAAAATTATTTATACACCAT 1-1-1- TaAaATtatttataCaCCAT 588_3 -20.40 11514 1-2-8- 1-1-4 588 TAAAATTATTTATACACCAT 4-1-2- TAAAaTTatttatACACcAT 588_4 -21.36 11514 6-4-1-2 588 TAAAATTATTTATACACCAT 1-3-3- TaaaATTatttatACAcCAT 588_5 -21.07 11514 6-3-1-3 588 TAAAATTATTTATACACCAT 2-1-4- TAaAATTatttataCACcAT 588_6 -21.36 11514 7-3-1-2 588 TAAAATTATTTATACACCAT 3-1-1- TAAaAtTatttataCAcCAT 588_7 -20.41 11514 1-1-7- 2-1-3 588 TAAAATTATTTATACACCAT 7-6-1- TAAAATTatttatAcacCAT 588_8 -20.85 11514 3-3 588 TAAAATTATTTATACACCAT 2-1-2- TAaAAttatttatacaCCAT 588_9 -19.82 11514 11-4 588 TAAAATTATTTATACACCAT 2-2-3- TAaaATTatttatACACcAT 588_10 -21.41 11514 6-4-1-2 588 TAAAATTATTTATACACCAT 1-1-1- TaAaATTatttatAcaCCAT 588_11 -21.15 11514 1-3-6- 1-2-4 588 TAAAATTATTTATACACCAT 2-1-2- TAaAAtTatttataCAcCAT 588_12 -20.41 11514 1-1-7- 2-1-3 588 TAAAATTATTTATACACCAT 3-2-2- TAAaaTTatttataCaCCAT 588_13 -21.86 11514 7-1-1-4 588 TAAAATTATTTATACACCAT 1-1-2- TaAAaTtatttatacACCAT 588_14 -19.68 11514 1-1-9-5 589 TAAAATTATTTATACACCA 1-1-2- TaAAaTtatttatACACCA 589_1 -20.31 11515 1-1-7-6 589 TAAAATTATTTATACACCA 1-2-3- TaaAATtatttaTaCACCA 589_2 -21.36 11515 6-1-1-5 589 TAAAATTATTTATACACCA 2-3-1- TAaaaTtatttatACACCA 589_3 -20.58 11515 7-6 589 TAAAATTATTTATACACCA 3-1-2- TAAaATtatttaTACAcCA 589_4 -21.36 11515 6-4-1-2 589 TAAAATTATTTATACACCA 4-1-1- TAAAaTtatttaTAcaCCA 589_5 -20.51 11515 6-2-2-3 589 TAAAATTATTTATACACCA 2-1-2- TAaAAttatttaTaCaCCA 589_6 -19.30 11515 7-1-1- 1-1-3 589 TAAAATTATTTATACACCA 1-3-2- TaaaATtatttaTAcaCCA 589_7 -19.40 11515 6-2-2-3 589 TAAAATTATTTATACACCA 5-8-2- TAAAAttatttatACaCCA 589_8 -19.77 11515 1-3 589 TAAAATTATTTATACACCA 3-1-2- TAAaATtatttatacACCA 589_9 -19.55 11515 9-4 589 TAAAATTATTTATACACCA 2-1-3- TAaAATtatttaTACAcCA 589_10 -21.36 11515 6-4-1-2 589 TAAAATTATTTATACACCA 3-1-2- TAAaATtatttaTACaCCA 589_11 -22.18 11515 6-3-1-3 589 TAAAATTATTTATACACCA 1-1-3- TaAAAttatttaTAcACCA 589_12 -19.78 11515 7-2-1-4 589 TAAAATTATTTATACACCA 2-2-1- TAaaAttatttaTaCaCCA 589_13 -18.76 11515 7-1-1- 1-1-3 589 TAAAATTATTTATACACCA 4-1-1- TAAAaTtatttataCACCA 589_14 -21.06 11515 8-5 590 ATATTGATTCAATTCCC 2-9-2- ATattgattcaATtCCC 590_1 -21.84 13226 1-3 590 ATATTGATTCAATTCCC 1-2-1- AtaTtgattcaATTCCC 590_2 -22.10 13226 7-6 590 ATATTGATTCAATTCCC 2-9-1- ATattgattcaAtTcCC 590_3 -18.59 13226 1-1-1-2 590 ATATTGATTCAATTCCC 1-1-2- AtATtgattcaaTTCCC 590_4 -21.87 13226 8-5 590 ATATTGATTCAATTCCC 1-2-2- AtaTTgattcaaTTcCC 590_5 -19.29 13226 7-2-1-2 590 ATATTGATTCAATTCCC 1-3-1- AtatTgattcaATtcCC 590_6 -18.59 13226 6-2-2-2 590 ATATTGATTCAATTCCC 1-2-2- AtaTTgattcaAttCCC 590_7 -20.66 13226 6-1-2-3 590 ATATTGATTCAATTCCC 1-1-1- AtAtTgattcaaTtCCC 590_8 -19.92 13226 1-1-7- 1-1-3 590 ATATTGATTCAATTCCC 1-1-1- AtAttgattcaAttCCC 590_9 -19.01 13226 8-1-2-3 590 ATATTGATTCAATTCCC 4-7-1- ATATtgattcaAttcCC 590_10 -20.60 13226 3-2 590 ATATTGATTCAATTCCC 3-1-1- ATAtTgattcaaTtcCC 590_11 -20.26 13226 7-1-2-2 590 ATATTGATTCAATTCCC 1-3-1- AtatTgattcaatTCCC 590_12 -20.37 13226 8-4 590 ATATTGATTCAATTCCC 2-1-1- ATaTtgattcaattCCC 590_13 -20.71 13226 10-3 590 ATATTGATTCAATTCCC 2-2-1- ATatTgattcaattCCC 590_14 -21.06 13226 9-3 590 ATATTGATTCAATTCCC 1-1-3- AtATTgattcaattcCC 590_15 -18.87 13226 10-2 590 ATATTGATTCAATTCCC 2-2-1- ATatTgattcaATtcCC 590_16 -20.26 13226 6-2-2-2 590 ATATTGATTCAATTCCC 3-8-1- ATAttgattcaAtTCCC 590_17 -22.71 13226 1-4 590 ATATTGATTCAATTCCC 1-1-3- AtATTgattcaAttCCC 590_18 -21.57 13226 6-1-2-3 590 ATATTGATTCAATTCCC 1-1-1- AtAtTgattcaaTTCCC 590_19 -21.42 13226 1-1-7-5 590 ATATTGATTCAATTCCC 2-1-1- ATaTtgattcaaTtCCC 590_20 -21.15 13226 8-1-1-3 591 GCACATTCTTTCTATACCT 1-1-1- GcAcAttctttctatacCT 591_1 -21.27 15113 1-1-12- 2 591 GCACATTCTTTCTATACCT 1-3-1- GcacAttctttctatacCT 591_2 -21.12 15113 12-2 592 GCACATTCTTTCTATACC 1-12- GcacattctttctAtaCC 592_1 -20.07 15114 1-2-2 592 GCACATTCTTTCTATACC 1-1-1- GcAcAttctttctataCC 592_2 -20.17 15114 1-1-11- 2 592 GCACATTCTTTCTATACC 1-3-1- GcacAttctttctataCC 592_3 -20.02 15114 11-2 592 GCACATTCTTTCTATACC 1-1-2- GcACattctttctatACC 592_4 -21.80 15114 11-3 592 GCACATTCTTTCTATACC 1-1-1- GcAcATtctttctAtACC 592_5 -22.11 15114 1-2-7- 1-1-3 592 GCACATTCTTTCTATACC 1-1-1- GcAcATtctttctAtaCC 592_6 -21.51 15114 1-2-7- 1-2-2 592 GCACATTCTTTCTATACC 1-15-2 GcacattctttctataCC 592_7 -19.97 15114 592 GCACATTCTTTCTATACC 1-4-1- GcacaTtctttctatACC 592_8 -21.01 15114 9-3 592 GCACATTCTTTCTATACC 1-4-1- GcacaTtctttctataCC 592_9 -20.41 15114 10-2 592 GCACATTCTTTCTATACC 2-11-1- GCacattctttctAtaCC 592_10 -22.39 15114 2-2 592 GCACATTCTTTCTATACC 1-1-1- GcAcAttctttctAtaCC 592_11 -20.27 15114 1-1-8- 1-2-2 592 GCACATTCTTTCTATACC 1-3-1- GcacAttctttctaTaCC 592_12 -20.89 15114 9-1-1-2 592 GCACATTCTTTCTATACC 1-1-1- GcAcAttctttctatACC 592_13 -20.77 15114 1-1-10- 3 592 GCACATTCTTTCTATACC 1-1-1- GcAcaTtctttctataCC 592_14 -20.56 15114 2-1-10- 2 593 TTATTTCCATTTATTTTCA 1-1-1- TtAtTtccatttaTTTtCA 593_1 -19.10 15563 1-1-8- 3-1-2 593 TTATTTCCATTTATTTTCA 1-2-2- TtaTTtccatttAtTtTCA 593_2 -19.27 15563 7-1-1- 1-1-3 593 TTATTTCCATTTATTTTCA 2-2-1- TTatTtccatttaTtTtCA 593_3 -18.92 15563 8-1-1- 1-1-2 593 TTATTTCCATTTATTTTCA 1-1-2- TtATttccatttaTttTCA 593_4 -19.41 15563 9-1-2-3 594 TTTATTTCCATTTATTTTCA 1-1-1- TtTatttccatttaTttTCA 594_1 -19.80 15563 11-1-2- 3 594 TTTATTTCCATTTATTTTCA 1-4-1- TttatTtccatttAtTttCA 594_2 -18.34 15563 7-1-1- 1-2-2 594 TTTATTTCCATTTATTTTCA 1-3-2- TttaTTtccatttatTTtCA 594_3 -20.01 15563 9-2-1-2 594 TTTATTTCCATTTATTTTCA 2-1-1- TTtAtTtccatttaTtTtCA 594_4 -19.60 15563 1-1-8- 1-1-1- 1-2 595 ATTTATTTCCATTTATTTTC 1-1-1- AtTtaTttccatttATTtTC 595_1 -19.05 15564 2-1-8- 3-1-2 595 ATTTATTTCCATTTATTTTC 1-3-2- AtttATttccattTattTTC 595_2 -19.03 15564 7-1-3-3 595 ATTTATTTCCATTTATTTTC 1-1-2- AtTTatttccatttAttTTC 595_3 -18.60 15564 10-1-2- 3 595 ATTTATTTCCATTTATTTTC 2-1-1- ATtTaTttccatttAtTtTC 595_4 -18.96 15564 1-1-8- 1-1-1- 1-2 596 TTTATTTCCATTTATTTTC 1-1-1- TtTaTttccatttATtTTC 596_1 -18.66 15564 1-1-8- 2-1-3 596 TTTATTTCCATTTATTTTC 3-2-1- TTTatTtccatttATTtTC 596_2 -19.84 15564 7-3-1-2 596 TTTATTTCCATTTATTTTC 2-2-2- TTtaTTtccatttAtTTTC 596_3 -19.12 15564 7-1-1-4 596 TTTATTTCCATTTATTTTC 5-7-1- TTTATttccattTattTTC 596_4 -21.30 15564 3-3 597 CCATTTATTTCCATTTATTT 1-1-1- CcAtttatttccatTTatTT 597_1 -19.89 15566 11-2-2- 2 597 CCATTTATTTCCATTTATTT 1-3-1- CcatTtatttccatTtAtTT 597_2 -19.00 15566 9-1-1- 1-1-2 597 CCATTTATTTCCATTTATTT 1-1-1- CcAttTatttccatTtaTTT 597_3 -20.33 15566 2-1-8- 1-2-3 597 CCATTTATTTCCATTTATTT 1-2-2- CcaTTtAtttccatttatTT 597_4 -19.64 15566 1-1-11- 2 598 TCCATTTATTTCCATTTATT 2-11- TCcatttatttccATttaTT 598_1 -21.22 15567 2-3-2 598 TCCATTTATTTCCATTTATT 2-2-1- TCcaTttatttccAtTtaTT 598_2 -20.71 15567 8-1-1- 1-2-2 598 TCCATTTATTTCCATTTATT 1-1-2- TcCAtttatttccAtttaTT 598_3 -20.63 15567 9-1-4-2 598 TCCATTTATTTCCATTTATT 2-1-1- TCcAtTtatttccatttATT 598_4 -21.18 15567 1-1-11- 3 599 TCCATTTATTTCCATTTAT 2-11- TCcatttatttccATttAT 599_1 -20.30 15568 2-2-2 599 TCCATTTATTTCCATTTAT 2-2-1- TCcaTttatttccAtTtAT 599_2 -19.80 15568 8-1-1- 1-1-2 599 TCCATTTATTTCCATTTAT 1-1-2- TcCAtttatttccAtttAT 599_3 -19.72 15568 9-1-3-2 599 TCCATTTATTTCCATTTAT 1-1-1- TcCaTTtatttccAtttAT 599_4 -19.50 15568 1-2-7- 1-3-2 600 TTCCATTTATTTCCATTTAT 1-1-1- TtCcaTttatttccAtTtAT 600_1 -20.12 15568 2-1-8- 1-1-1- 1-2 600 TTCCATTTATTTCCATTTAT 1-3-1- TtccAtttatttccaTTtAT 600_2 -19.86 15568 10-2-1- 2 600 TTCCATTTATTTCCATTTAT 1-1-1- TtCcatTtatttccAtttAT 600_3 -19.68 15568 3-1-7- 1-3-2 600 TTCCATTTATTTCCATTTAT 1-1-1- TtCcATttatttccAtttAT 600_4 -20.68 15568 1-2-8- 1-3-2 601 TTTCCATTTATTTCCATTTA 1-4-1- TttccAtttatttCcaTtTA 601_1 -20.53 15569 7-1-2- 1-1-2 601 TTTCCATTTATTTCCATTTA 2-2-1- TTtcCatttatttccatTTA 601_2 -21.47 15569 12-3 601 TTTCCATTTATTTCCATTTA 1-2-1- TttCcaTttatttccAttTA 601_3 -20.53 15569 2-1-8- 1-2-2 601 TTTCCATTTATTTCCATTTA 1-4-1- TttccAtttatttccAttTA 601_4 -19.37 15569 9-1-2-2 602 CTTTCCATTTATTTCCATT 1-11- CtttccatttatTtCcATT 602_1 -21.20 15571 1-1-1- 1-3 602 CTTTCCATTTATTTCCATT 2-2-1- CTttCcatttatttCcaTT 602_2 -22.00 15571 9-1-2-2 602 CTTTCCATTTATTTCCATT 1-4-1- CtttcCatttatttcCaTT 602_3 -20.42 15571 9-1-1-2 602 CTTTCCATTTATTTCCATT 1-3-1- CtttCcatttatttccATT 602_4 -20.89 15571 11-3 603 ATCTTTCCATTTATTTCCAT 1-2-1- AtcTttccatttatttCcAT 603_1 -21.24 15572 12-1-1- 2 603 ATCTTTCCATTTATTTCCAT 1-3-1- AtctTtCcatttatTtccAT 603_2 -21.33 15572 1-1-7- 1-3-2 603 ATCTTTCCATTTATTTCCAT 1-5-1- AtctttCcatttaTttccAT 603_3 -21.16 15572 6-1-4-2 603 ATCTTTCCATTTATTTCCAT 1-16-3 AtctttccatttatttcCAT 603_4 -21.95 15572 604 TCTTTCCATTTATTTCCAT 2-13- TCtttccatttatttCcAT 604_1 -21.57 15572 1-1-2 604 TCTTTCCATTTATTTCCAT 1-2-1- TctTtCcatttatTtCcAT 604_2 -21.35 15572 1-1-7- 1-1-1- 1-2 604 TCTTTCCATTTATTTCCAT 2-14-3 TCtttccatttatttcCAT 604_3 -22.80 15572 604 TCTTTCCATTTATTTCCAT 2-3-1- TCtttCcatttatttccAT 604_4 -21.57 15572 11-2 605 ATCTTTCCATTTATTTCCA 1-2-1- AtcTttccatttatTtcCA 605_1 -20.70 15573 10-1-2- 2 605 ATCTTTCCATTTATTTCCA 1-3-1- AtctTtccatttaTttcCA 605_2 -20.63 15573 8-1-3-2 605 ATCTTTCCATTTATTTCCA 1-1-1- AtCtttccatttatttcCA 605_3 -20.86 15573 14-2 605 ATCTTTCCATTTATTTCCA 1-4-1- AtcttTccatttattTcCA 605_4 -20.63 15573 9-1-1-2 606 TATCTTTCCATTTATTTCCA 1-4-1- TatctTtccatttaTTtcCA 606_1 -22.54 15573 8-2-2-2 606 TATCTTTCCATTTATTTCCA 2-16-2 TAtctttccatttatttcCA 606_2 -22.12 15573 606 TATCTTTCCATTTATTTCCA 1-2-1- TatCtttccatttatttcCA 606_3 -21.97 15573 14-2 606 TATCTTTCCATTTATTTCCA 1-17-2 TatctttccatttatttcCA 606_4 -20.99 15573 607 TATCTTTCCATTTATTTCC 2-12- TAtctttccatttaTttCC 607_1 -21.63 15574 1-2-2 607 TATCTTTCCATTTATTTCC 1-2-1- TatCtttccatttatttCC 607_2 -21.04 15574 13-2 607 TATCTTTCCATTTATTTCC 1-2-2- TatCTttccatttatttCC 607_3 -22.23 15574 12-2 607 TATCTTTCCATTTATTTCC 1-4-1- TatctTtccatttatTtCC 607_4 -20.66 15574 9-1-1-2 608 AAATCTCAACTACCATTTTT 1-1-1- AaAtctCaactaccATTtTT 608_1 -19.53 25248 3-1-7- 3-1-2 608 AAATCTCAACTACCATTTTT 3-1-1- AAAtCtcaactaccATtTTT 608_2 -20.58 25248 9-2-1-3 608 AAATCTCAACTACCATTTTT 1-3-1- AaatCtcaactacCaTTTTT 608_3 -20.56 25248 8-1-1-5 608 AAATCTCAACTACCATTTTT 1-1-1- AaAtcTcaactacCAttTTT 608_4 -20.20 25248 2-1-7- 2-2-3 608 AAATCTCAACTACCATTTTT 1-3-1- AaatCtCaactacCaTttTT 608_5 -19.10 25248 1-1-6- 1-1-1- 2-2 608 AAATCTCAACTACCATTTTT 2-3-2- AAatcTCaactacCatTTTT 608_6 -21.04 25248 6-1-2-4 608 AAATCTCAACTACCATTTTT 2-1-2- AAaTCtCaactaccAtttTT 608_7 -19.79 25248 1-1-7- 1-3-2 608 AAATCTCAACTACCATTTTT 1-1-3- AaATCtcaactaccatTtTT 608_8 -19.97 25248 11-1-1- 2 608 AAATCTCAACTACCATTTTT 3-1-1- AAAtCtCaactaccattTTT 608_9 -19.95 25248 1-1-10- 3 609 AAAATCTCAACTACCATTTT 1-12- AaaatctcaactaCCATtTT 609_1 -21.31 25249 4-1-2 609 AAAATCTCAACTACCATTTT 3-11- AAAatctcaactacCAtTTT 609_2 -19.57 25249 2-1-3 609 AAAATCTCAACTACCATTTT 2-1-1- AAaAtCtcaactacCAtTTT 609_3 -20.33 25249 1-1-8- 2-1-3 609 AAAATCTCAACTACCATTTT 1-1-4- AaAATCtcaactaccAttTT 609_4 -19.46 25249 9-1-2-2 609 AAAATCTCAACTACCATTTT 1-1-2- AaAAtcTcaactacCAttTT 609_5 -19.13 25249 2-1-7- 2-2-2 609 AAAATCTCAACTACCATTTT 4-1-1- AAAAtCtcaactaCcaTTTT 609_6 -20.75 25249 7-1-2-4 609 AAAATCTCAACTACCATTTT 1-1-1- AaAatCtcaactacCaTTTT 609_7 -19.30 25249 2-1-8- 1-1-4 609 AAAATCTCAACTACCATTTT 1-2-3- AaaATCtcaactaCcAtTTT 609_8 -20.51 25249 7-1-1- 1-1-3 609 AAAATCTCAACTACCATTTT 2-2-2- AAaaTCtcaactaccaTtTT 609_9 -18.72 25249 10-1-1- 2 610 AAAATCTCAACTACCATTT 1-4-1- AaaatCtcaactACCAtTT 610_1 -20.63 25250 6-4-1-2 610 AAAATCTCAACTACCATTT 3-10-6 AAAatctcaactaCCATTT 610_2 -21.90 25250 610 AAAATCTCAACTACCATTT 6-6-2- AAAATCtcaactACcaTTT 610_3 -21.46 25250 2-3 610 AAAATCTCAACTACCATTT 2-2-2- AAaaTCtcaactaCCaTTT 610_4 -21.18 25250 7-2-1-3 610 AAAATCTCAACTACCATTT 6-7-2- AAAATCtcaactaCCatTT 610_5 -22.10 25250 2-2 610 AAAATCTCAACTACCATTT 2-1-1- AAaAtCtcaactacCATTT 610_6 -20.27 25250 1-1-8-5 610 AAAATCTCAACTACCATTT 1-1-1- AaAaTCtcaactacCATTT 610_7 -20.88 25250 1-2-8-5 610 AAAATCTCAACTACCATTT 1-1-2- AaAAtCtcaactacCAtTT 610_8 -18.51 25250 1-1-8- 2-1-2 610 AAAATCTCAACTACCATTT 6-9-4 AAAATCtcaactaccATTT 610_9 -20.94 25250 611 GAAAATCTCAACTACCATT 1-1-3- GaAAAtctcaacTacCATT 611_1 -20.48 25251 7-1-2-4 611 GAAAATCTCAACTACCATT 1-1-2- GaAAatctcaacTaCcATT 611_2 -18.75 25251 8-1-1- 1-1-3 611 GAAAATCTCAACTACCATT 3-1-1- GAAaAtctcaactacCATT 611_3 -20.73 25251 10-4 611 GAAAATCTCAACTACCATT 2-1-2- GAaAAtctcaactacCATT 611_4 -20.73 25251 10-4 611 GAAAATCTCAACTACCATT 2-2-1- GAaaAtctcaacTaccaTT 611_5 -18.28 25251 7-1-4-2 611 GAAAATCTCAACTACCATT 2-12-5 GAaaatctcaactaCCATT 611_6 -22.25 25251 611 GAAAATCTCAACTACCATT 4-10- GAAAatctcaactaCCaTT 611_7 -21.06 25251 2-1-2 611 GAAAATCTCAACTACCATT 4-10- GAAAatctcaactaCcATT 611_8 -19.73 25251 1-1-3 611 GAAAATCTCAACTACCATT 5-12-2 GAAAAtctcaactaccaTT 611_9 -18.61 25251 612 TGAAAATCTCAACTACCAT 1-4-1- TgaaaAtctcaaCtACcAT 612_1 -18.43 25252 6-1-1- 2-1-2 612 TGAAAATCTCAACTACCAT 2-1-2- TGaAAatctcaaCtaCcAT 612_2 -19.46 25252 7-1-2- 1-1-2 612 TGAAAATCTCAACTACCAT 1-1-2- TgAAaatctcaaCtaCcAT 612_3 -18.58 25252 8-1-2- 1-1-2 612 TGAAAATCTCAACTACCAT 1-2-1- TgaAaAtctcaaCtacCAT 612_4 -19.40 25252 1-1-6- 1-3-3 612 TGAAAATCTCAACTACCAT 1-3-2- TgaaAAtctcaactacCAT 612_5 -18.60 25252 10-3 612 TGAAAATCTCAACTACCAT 1-11- TgaaaatctcaaCtaCCAT 612_6 -21.11 25252 1-2-4 612 TGAAAATCTCAACTACCAT 3-1-2- TGAaAAtctcaaCtaccAT 612_7 -20.39 25252 6-1-4-2 612 TGAAAATCTCAACTACCAT 1-1-1- TgAaAatctcaaCtacCAT 612_8 -19.60 25252 1-1-7- 1-3-3 612 TGAAAATCTCAACTACCAT 4-12-3 TGAAaatctcaactacCAT 612_9 -21.07 25252 613 ATCATTCTCAACAATTAAA 4-8-7 ATCAttctcaacAATTAAA 613_1 -20.89 30599 613 ATCATTCTCAACAATTAAA 1-1-4- AtCATTctcaacAATTAAA 613_2 -21.09 30599 6-7 613 ATCATTCTCAACAATTAAA 5-7-2- ATCATtctcaacAAtTaAA 613_3 -19.03 30599 1-1-1-2 613 ATCATTCTCAACAATTAAA 5-8-2- ATCATtctcaacaATtaAA 613_4 -19.28 30599 2-2 613 ATCATTCTCAACAATTAAA 4-1-1- ATCAtTctcaacaaTTAAA 613_5 -19.86 30599 8-5 613 ATCATTCTCAACAATTAAA 5-7-4- ATCATtctcaacAATTaAA 613_6 -20.79 30599 1-2 613 ATCATTCTCAACAATTAAA 4-8-1- ATCAttctcaacAaTTAAA 613_7 -19.56 30599 1-5 613 ATCATTCTCAACAATTAAA 1-1-4- AtCATTctcaacAaTTAAA 613_8 -19.76 30599 6-1-1-5 613 ATCATTCTCAACAATTAAA 4-1-1- ATCAtTctcaacaATTaAA 613_9 -19.64 30599 7-3-1-2 613 ATCATTCTCAACAATTAAA 5-8-1- ATCATtctcaacaAtTAAA 613_10 -20.11 30599 1-4 614 ATCATTCTCAACAATTAA 4-8-6 ATCAttctcaacAATTAA 614_1 -20.14 30600 614 ATCATTCTCAACAATTAA 1-1-4- AtCATTctcaacAATTAA 614_2 -20.34 30600 6-6 614 ATCATTCTCAACAATTAA 5-8-1- ATCATtctcaacaAtTAA 614_3 -19.36 30600 1-3 614 ATCATTCTCAACAATTAA 4-8-1- ATCAttctcaacAaTTAA 614_4 -18.81 30600 1-4 614 ATCATTCTCAACAATTAA 5-8-5 ATCATtctcaacaATTAA 614_5 -21.12 30600 614 ATCATTCTCAACAATTAA 5-7-1- ATCATtctcaacAatTAA 614_6 -19.11 30600 2-3 614 ATCATTCTCAACAATTAA 3-10-5 ATCattctcaacaATTAA 614_7 -18.40 30600 614 ATCATTCTCAACAATTAA 4-9-1- ATCAttctcaacaAtTAA 614_8 -18.11 30600 1-3 614 ATCATTCTCAACAATTAA 4-1-1- ATCAtTctcaacaaTTAA 614_9 -19.11 30600 8-4 614 ATCATTCTCAACAATTAA 1-1-3- AtCATtctcaacaaTTAA 614_10 -18.05 30600 9-4 615 GATCATTCTCAACAATTAA 2-3-1- GAtcaTtctcaaCAaTTAA 615_1 -20.54 30600 6-2-1-4 615 GATCATTCTCAACAATTAA 1-2-2- GatCAttctcaaCaaTTAA 615_2 -19.04 30600 7-1-2-4 615 GATCATTCTCAACAATTAA 2-1-3- GAtCATtctcaaCAAttAA 615_3 -21.29 30600 6-3-2-2 615 GATCATTCTCAACAATTAA 2-1-2- GAtCAttctcaacAAtTAA 615_4 -19.70 30600 8-2-1-3 615 GATCATTCTCAACAATTAA 5-8-1- GATCAttctcaacAaTtAA 615_5 -19.79 30600 1-1-1-2 615 GATCATTCTCAACAATTAA 4-8-3- GATCattctcaaCAAttAA 615_6 -20.50 30600 2-2 615 GATCATTCTCAACAATTAA 1-2-3- GatCATtctcaaCAatTAA 615_7 -20.82 30600 6-2-2-3 615 GATCATTCTCAACAATTAA 2-2-2- GAtcATtctcaaCaATTAA 615_8 -21.04 30600 6-1-1-5 615 GATCATTCTCAACAATTAA 2-1-1- GAtCattctcaaCaaTTAA 615_9 -19.28 30600 8-1-2-4 615 GATCATTCTCAACAATTAA 1-1-3- GaTCAttctcaacaAtTAA 615_10 -18.85 30600 9-1-1-3 616 AGATCATTCTCAACAATTA 1-1-1- AgAtcAttctcaaCAAtTA 616_1 -19.10 30601 2-1-7- 3-1-2 616 AGATCATTCTCAACAATTA 1-3-1- AgatCattctcaaCAaTTA 616_2 -19.65 30601 8-2-1-3 616 AGATCATTCTCAACAATTA 1-3-2- AgatCAttctcaAcAatTA 616_3 -18.49 30601 6-1-1- 1-2-2 616 AGATCATTCTCAACAATTA 1-1-1- AgAtCAttctcaacaatTA 616_4 -18.49 30601 1-2-11- 2 616 AGATCATTCTCAACAATTA 1-1-1- AgAtcAttctcaacaATTA 616_5 -18.49 30601 2-1-9-4 616 AGATCATTCTCAACAATTA 1-3-2- AgatCAttctcaAcAATTA 616_6 -20.76 30601 6-1-1-5 616 AGATCATTCTCAACAATTA 2-2-1- AGatCattctcaaCAAtTA 616_7 -20.47 30601 8-3-1-2 616 AGATCATTCTCAACAATTA 3-2-1- AGAtcAttctcaaCaaTTA 616_8 -20.51 30601 7-1-2-3 616 AGATCATTCTCAACAATTA 1-2-3- AgaTCAttctcaaCaatTA 616_9 -19.80 30601 7-1-3-2 616 AGATCATTCTCAACAATTA 1-1-1- AgAtCAttctcaacAAtTA 616_10 -19.08 30601 1-2-8- 2-1-2 617 GATCATTCTCAACAATTA 2-3-1- GAtcaTtctcaaCAATTA 617_1 -21.11 30601 6-6 617 GATCATTCTCAACAATTA 2-1-2- GAtCAttctcaacAATTA 617_2 -20.71 30601 8-5 617 GATCATTCTCAACAATTA 2-2-2- GAtcATtctcaaCAatTA 617_3 -19.70 30601 6-2-2-2 617 GATCATTCTCAACAATTA 1-1-3- GaTCAttctcaaCaAtTA 617_4 -18.78 30601 7-1-1- 1-1-2 617 GATCATTCTCAACAATTA 2-1-2- GAtCAttctcaacaaTTA 617_5 -19.31 30601 10-3 617 GATCATTCTCAACAATTA 2-1-1- GAtCaTtctcaaCAAtTA 617_6 -20.02 30601 1-1-6- 3-1-2 617 GATCATTCTCAACAATTA 2-1-2- GAtCAttctcaaCAatTA 617_7 -20.53 30601 7-2-2-2 617 GATCATTCTCAACAATTA 2-1-3- GAtCATtctcaaCaaTTA 617_8 -21.24 30601 6-1-2-3 617 GATCATTCTCAACAATTA 2-2-1- GAtcAttctcaacAATTA 617_9 -18.63 30601 8-5 617 GATCATTCTCAACAATTA 1-1-3- GaTCAttctcaacaAtTA 617_10 -18.10 30601 9-1-1-2 618 AGATCATTCTCAACAATT 1-3-2- AgatCAttctcaACAATT 618_1 -21.03 30602 6-6 618 AGATCATTCTCAACAATT 1-1-1- AgAtCAttctcaaCAATT 618_2 -20.70 30602 1-2-7-5 618 AGATCATTCTCAACAATT 1-1-4- AgATCAttctcaAcaaTT 618_3 -19.56 30602 6-1-3-2 618 AGATCATTCTCAACAATT 3-1-1- AGAtCattctcaacAATT 618_4 -19.61 30602 9-4 618 AGATCATTCTCAACAATT 2-1-3- AGaTCAttctcaacaaTT 618_5 -19.09 30602 10-2 618 AGATCATTCTCAACAATT 1-2-3- AgaTCAttctcaAcaaTT 618_6 -18.25 30602 6-1-3-2 618 AGATCATTCTCAACAATT 2-2-2- AGatCAttctcaaCAaTT 618_7 -20.14 30602 7-2-1-2 618 AGATCATTCTCAACAATT 1-1-1- AgAtCAttctcaaCaATT 618_8 -19.02 30602 1-2-7- 1-1-3 618 AGATCATTCTCAACAATT 1-2-3- AgaTCAttctcaacAATT 618_9 -19.23 30602 8-4 618 AGATCATTCTCAACAATT 3-1-1- AGAtCattctcaacaATT 618_10 -19.34 30602 10-3 619 GATCATTCTCAACAATT 2-1-2- GAtCAttctcaACAATT 619_1 -21.40 30602 6-6 619 GATCATTCTCAACAATT 1-1-3- GaTCAttctcaaCAATT 619_2 -19.99 30602 7-5 619 GATCATTCTCAACAATT 5-7-1- GATCAttctcaaCaaTT 619_3 -19.69 30602 2-2 619 GATCATTCTCAACAATT 5-6-1- GATCAttctcaAcAATT 619_4 -20.83 30602 1-4 619 GATCATTCTCAACAATT 2-1-2- GAtCAttctcaaCAATT 619_5 -20.57 30602 7-5 619 GATCATTCTCAACAATT 5-6-1- GATCAttctcaAcaaTT 619_6 -19.43 30602 3-2 619 GATCATTCTCAACAATT 4-8-5 GATCattctcaaCAATT 619_7 -21.04 30602 619 GATCATTCTCAACAATT 1-1-3- GaTCAttctcaaCAaTT 619_8 -18.67 30602 7-2-1-2 619 GATCATTCTCAACAATT 5-7-1- GATCAttctcaaCaATT 619_9 -20.82 30602 1-3 619 GATCATTCTCAACAATT 2-1-2- GAtCAttctcaacAATT 619_10 -18.48 30602 8-4 620 AAGATCATTCTCAACAAT 4-1-1- AAGAtCattctcAaCAAT 620_1 -20.71 30603 6-1-1-4 620 AAGATCATTCTCAACAAT 4-9-5 AAGAtcattctcaACAAT 620_2 -20.79 30603 620 AAGATCATTCTCAACAAT 2-2-2- AAgaTCattctcAACAAT 620_3 -19.88 30603 6-6 620 AAGATCATTCTCAACAAT 4-1-1- AAGAtCattctcaACaAT 620_4 -19.77 30603 7-2-1-2 620 AAGATCATTCTCAACAAT 2-1-3- AAgATCattctcaaCAAT 620_5 -20.10 30603 8-4 620 AAGATCATTCTCAACAAT 4-1-1- AAGAtCattctcAAcaAT 620_6 -18.96 30603 6-2-2-2 620 AAGATCATTCTCAACAAT 3-1-2- AAGaTCattctcAaCAAT 620_7 -20.12 30603 6-1-1-4 620 AAGATCATTCTCAACAAT 2-1-3- AAgATCattctcAaCAAT 620_8 -20.17 30603 6-1-1-4 620 AAGATCATTCTCAACAAT 1-1-1- AaGatCattctcaACAAT 620_9 -18.21 30603 2-1-7-5 620 AAGATCATTCTCAACAAT 4-1-1- AAGAtCattctcaaCAAT 620_10 -20.63 30603 8-4 621 AAAGATCATTCTCAACAA 1-1-1- AaAgatcattctCAACAA 621_1 -18.13 30604 9-6 621 AAAGATCATTCTCAACAA 1-1-3- AaAGAtcattctCAaCAA 621_2 -20.08 30604 7-2-1-3 621 AAAGATCATTCTCAACAA 1-3-2- AaagATcattctCAaCAA 621_3 -18.11 30604 6-2-1-3 621 AAAGATCATTCTCAACAA 1-2-2- AaaGAtcattctCaACAA 621_4 -18.07 30604 7-1-1-4 621 AAAGATCATTCTCAACAA 5-10-3 AAAGAtcattctcaaCAA 621_5 -18.65 30604 621 AAAGATCATTCTCAACAA 1-1-3- AaAGAtcattctCAAcAA 621_6 -18.59 30604 7-3-1-2 621 AAAGATCATTCTCAACAA 4-8-2- AAAGatcattctCAaCAA 621_7 -19.10 30604 1-3 621 AAAGATCATTCTCAACAA 3-1-1- AAAgAtcattctCAaCAA 621_8 -18.35 30604 7-2-1-3 621 AAAGATCATTCTCAACAA 1-1-2- AaAGatcattctCAaCAA 621_9 -18.37 30604 8-2-1-3 621 AAAGATCATTCTCAACAA 1-2-2- AaaGAtcattctCAaCAA 621_10 -18.74 30604 7-2-1-3 621 AAAGATCATTCTCAACAA 5-7-1- AAAGAtcattctCaaCAA 621_11 -19.32 30604 2-3 622 CAAAGATCATTCTCAACA 1-1-2- CaAAgatcattcTCAACA 622_1 -20.93 30605 8-6 622 CAAAGATCATTCTCAACA 2-1-1- CAaAgatcattctCAACA 622_2 -20.68 30605 9-5 622 CAAAGATCATTCTCAACA 1-4-1- CaaagAtcattctCAACA 622_3 -18.86 30605 7-5 622 CAAAGATCATTCTCAACA 4-1-1- CAAAgAtcattctCaaCA 622_4 -19.40 30605 7-1-2-2 622 CAAAGATCATTCTCAACA 3-1-2- CAAaGAtcattctcaaCA 622_5 -19.67 30605 10-2 622 CAAAGATCATTCTCAACA 4-8-2- CAAAgatcattcTCaaCA 622_6 -20.10 30605 2-2 622 CAAAGATCATTCTCAACA 1-1-2- CaAAgAtcattctCAACA 622_7 -20.23 30605 1-1-7-5 622 CAAAGATCATTCTCAACA 2-1-1- CAaAgatcattctCAaCA 622_8 -19.66 30605 9-2-1-2 622 CAAAGATCATTCTCAACA 3-2-1- CAAagAtcattctCaACA 622_9 -19.21 30605 7-1-1-3 622 CAAAGATCATTCTCAACA 1-3-2- CaaaGAtcattctCaaCA 622_10 -18.30 30605 7-1-2-2 623 CAAAGATCATTCTCAAC 3-8-6 CAAagatcattCTCAAC 623_1 -19.95 30606 623 CAAAGATCATTCTCAAC 2-1-1- CAaAgatcattCTCAAC 623_2 -20.23 30606 7-6 623 CAAAGATCATTCTCAAC 2-2-1- CAaaGatcattCTCAAC 623_3 -20.15 30606 6-6 623 CAAAGATCATTCTCAAC 1-2-2- CaaAGatcattCTCAAC 623_4 -20.00 30606 6-6 623 CAAAGATCATTCTCAAC 5-6-1- CAAAGatcattCtCAAC 623_5 -20.35 30606 1-4 623 CAAAGATCATTCTCAAC 4-7-3- CAAAgatcattCTCaAC 623_6 -19.28 30606 1-2 623 CAAAGATCATTCTCAAC 3-1-1- CAAaGatcattCtCAAC 623_7 -18.81 30606 6-1-1-4 623 CAAAGATCATTCTCAAC 2-1-1- CAaAgatcattCtCAAC 623_8 -18.36 30606 7-1-1-4 623 CAAAGATCATTCTCAAC 1-2-2- CaaAGatcattCtCAAC 623_9 -18.12 30606 6-1-1-4 623 CAAAGATCATTCTCAAC 4-8-5 CAAAgatcattcTCAAC 623_10 -19.31 30606 624 CTCAAAGATCATTCTCA 1-2-1- CtcAaagatcaTTCTCA 624_1 -20.57 30608 7-6 624 CTCAAAGATCATTCTCA 1-1-1- CtCaAagatcatTCtCA 624_2 -18.69 30608 1-1-7- 2-1-2 624 CTCAAAGATCATTCTCA 1-1-2- CtCAaagatcaTtcTCA 624_3 -19.51 30608 7-1-2-3 624 CTCAAAGATCATTCTCA 3-10- CTCaaagatcattCtCA 624_4 -19.23 30608 1-1-2 624 CTCAAAGATCATTCTCA 1-1-3- CtCAAagatcattCTCA 624_5 -21.26 30608 8-4 624 CTCAAAGATCATTCTCA 1-1-3- CtCAAagatcaTtCtCA 624_6 -19.82 30608 6-1-1- 1-1-2 624 CTCAAAGATCATTCTCA 4-7-1- CTCAaagatcaTtctCA 624_7 -20.18 30608 3-2 624 CTCAAAGATCATTCTCA 1-2-2- CtcAAagatcatTCTCA 624_8 -20.16 30608 7-5 624 CTCAAAGATCATTCTCA 1-1-2- CtCAaagatcatTCtCA 624_9 -19.83 30608 8-2-1-2 624 CTCAAAGATCATTCTCA 3-10-4 CTCaaagatcattCTCA 624_10 -21.11 30608 625 TACACTTAATTATACTTCCA 1-2-1- TacAcTtaattatACttcCA 625_1 -20.33 30666 1-1-7- 2-3-2 625 TACACTTAATTATACTTCCA 1-2-1- TacActTaattatActtcCA 625_2 -19.15 30666 2-1-6- 1-4-2 625 TACACTTAATTATACTTCCA 1-4-1- TacacTtaattatAcTtcCA 625_3 -19.30 30666 7-1-1- 1-2-2 625 TACACTTAATTATACTTCCA 1-1-1- TaCacTTaattatActtcCA 625_4 -20.71 30666 2-2-6- 1-4-2 625 TACACTTAATTATACTTCCA 1-1-1- TaCactTaattatacTtcCA 625_5 -20.00 30666 3-1-8- 1-2-2 625 TACACTTAATTATACTTCCA 1-2-1- TacAcTTaattatacTtcCA 625_6 -20.50 30666 1-2-8- 1-2-2 625 TACACTTAATTATACTTCCA 1-2-1- TacActtaattatacttCCA 625_7 -20.60 30666 13-3 625 TACACTTAATTATACTTCCA 1-4-1- TacacTtaattatacttCCA 625_8 -20.96 30666 11-3 625 TACACTTAATTATACTTCCA 2-1-1- TAcAcTtaattatacttcCA 625_9 -19.97 30666 1-1-12- 2 625 TACACTTAATTATACTTCCA 1-1-1- TaCacTtaattatACttcCA 625_10 -20.87 30666 2-1-7- 2-3-2 625 TACACTTAATTATACTTCCA 1-2-1- TacAcTTaattatAcTtcCA 625_11 -20.69 30666 1-2-6- 1-1-1- 2-2 625 TACACTTAATTATACTTCCA 1-2-1- TacAcTtaattatacTtCCA 625_12 -21.63 30666 1-1-9- 1-1-3 625 TACACTTAATTATACTTCCA 1-1-1- TaCactTaattatacttCCA 625_13 -21.86 30666 3-1-10- 3 625 TACACTTAATTATACTTCCA 2-1-2- TAcACtTaattatacttcCA 625_14 -21.58 30666 1-1-11- 2 626 TTACACTTAATTATACTTCC 1-3-1- TtacAcTtaattatACttCC 626_1 -19.98 30667 1-1-7- 2-2-2 626 TTACACTTAATTATACTTCC 1-5-1- TtacacTtaattatAcTtCC 626_2 -18.96 30667 7-1-1- 1-1-2 626 TTACACTTAATTATACTTCC 2-4-1- TTacacTtaattatacttCC 626_3 -19.49 30667 11-2 626 TTACACTTAATTATACTTCC 1-5-1- TtacacTtaattatacTTCC 626_4 -20.26 30667 9-4 626 TTACACTTAATTATACTTCC 1-1-1- TtAcacTtaattataCttCC 626_5 -19.43 30667 3-1-8- 1-2-2 626 TTACACTTAATTATACTTCC 1-1-2- TtACacTtaattatActtCC 626_6 -19.72 30667 2-1-7- 1-3-2 626 TTACACTTAATTATACTTCC 3-1-1- TTAcActtaattatactTCC 626_7 -21.33 30667 12-3 626 TTACACTTAATTATACTTCC 1-1-1- TtAcAcTtaattatacTtCC 626_8 -19.10 30667 1-1-1- 1-9-1- 1-2 626 TTACACTTAATTATACTTCC 1-2-2- TtaCAcTtaattatacttCC 626_9 -20.49 30667 1-1-11- 2 626 TTACACTTAATTATACTTCC 1-5-1- TtacacTtaattatACtTCC 626_10 -20.82 30667 7-2-1-3 626 TTACACTTAATTATACTTCC 4-2-1- TTACacTtaattatActtCC 626_11 -21.99 30667 7-1-3-2 626 TTACACTTAATTATACTTCC 1-1-1- TtAcACTtaattataCttCC 626_12 -21.65 30667 1-3-8- 1-2-2 626 TTACACTTAATTATACTTCC 2-1-2- TTaCActtaattatacTTCC 626_13 -23.23 30667 11-4 626 TTACACTTAATTATACTTCC 2-2-1- TTacAcTtaattatacTtCC 626_14 -20.15 30667 1-1-9- 1-1-2 627 TTTACACTTAATTATACTTC 2-1-2- TTtACacttaattAtACTTC 627_1 -20.02 30668 8-1-1-5 627 TTTACACTTAATTATACTTC 2-3-1- TTtacActtaattATACtTC 627_2 -19.89 30668 7-4-1-2 627 TTTACACTTAATTATACTTC 1-2-1- TttAcActtaattATaCTTC 627_3 -19.35 30668 1-1-7- 2-1-4 627 TTTACACTTAATTATACTTC 1-1-3- TtTACacttaattATActTC 627_4 -20.58 30668 8-3-2-2 627 TTTACACTTAATTATACTTC 3-2-1- TTTacActtaattATAcTTC 627_5 -20.76 30668 7-3-1-3 627 TTTACACTTAATTATACTTC 1-3-2- TttaCActtaattATacTTC 627_6 -19.58 30668 7-2-2-3 627 TTTACACTTAATTATACTTC 3-2-1- TTTacActtaattATaCTTC 627_7 -21.21 30668 7-2-1-4 627 TTTACACTTAATTATACTTC 3-1-1- TTTaCacttaattAtaCTTC 627_8 -20.07 30668 8-1-2-4 627 TTTACACTTAATTATACTTC 6-7-1- TTTACActtaattAtactTC 627_9 -20.56 30668 4-2 627 TTTACACTTAATTATACTTC 4-1-1- TTTAcActtaattATACtTC 627_10 -22.36 30668 7-4-1-2 627 TTTACACTTAATTATACTTC 3-1-1- TTTaCaCttaattATAcTTC 627_11 -22.29 30668 1-1-6- 3-1-3 627 TTTACACTTAATTATACTTC 2-1-3- TTtACActtaattATActTC 627_12 -21.19 30668 7-3-2-2 627 TTTACACTTAATTATACTTC 3-1-2- TTTaCActtaattATaCTTC 627_13 -23.30 30668 7-2-1-4 627 TTTACACTTAATTATACTTC 1-1-4- TtTACActtaattAtaCTTC 627_14 -21.94 30668 7-1-2-4 628 ATTTACACTTAATTATACTT 2-1-1- ATtTacActtaatTATaCTT 628_1 -21.21 30669 2-1-6- 3-1-3 628 ATTTACACTTAATTATACTT 3-1-1- ATTtAcacttaatTAtACTT 628_2 -20.27 30669 8-2-1-4 628 ATTTACACTTAATTATACTT 1-1-2- AtTTacActtaatTATAcTT 628_3 -20.33 30669 2-1-6- 4-1-2 628 ATTTACACTTAATTATACTT 1-3-1- AtttAcActtaattATACTT 628_4 -19.30 30669 1-1-7-6 628 ATTTACACTTAATTATACTT 2-2-2- ATttACacttaatTATacTT 628_5 -19.94 30669 7-3-2-2 628 ATTTACACTTAATTATACTT 4-1-2- ATTTaCActtaatTAtacTT 628_6 -21.29 30669 6-2-3-2 628 ATTTACACTTAATTATACTT 1-1-4- AtTTACacttaatTaTacTT 628_7 -19.33 30669 7-1-1- 1-2-2 628 ATTTACACTTAATTATACTT 2-2-3- ATttACActtaatTatACTT 628_8 -20.97 30669 6-1-2-4 628 ATTTACACTTAATTATACTT 4-2-1- ATTTacActtaatTataCTT 628_9 -19.73 30669 6-1-3-3 628 ATTTACACTTAATTATACTT 1-1-2- AtTTaCActtaatTATAcTT 628_10 -22.43 30669 1-2-6- 4-1-2 628 ATTTACACTTAATTATACTT 3-2-2- ATTtaCActtaatTAtaCTT 628_11 -21.72 30669 6-2-2-3 628 ATTTACACTTAATTATACTT 1-2-4- AttTACActtaatTAtaCTT 628_12 -22.02 30669 6-2-2-3 628 ATTTACACTTAATTATACTT 2-1-1- ATtTaCActtaatTaTACTT 628_13 -23.00 30669 1-2-6- 1-1-5 628 ATTTACACTTAATTATACTT 5-8-1- ATTTAcacttaatTaTaCTT 628_14 -21.68 30669 1-1-1-3 629 TTCTACTATACTTTCCTCT 1-3-1- TtctActatactTtCctCT 629_1 -21.04 30711 7-1-1- 1-2-2 629 TTCTACTATACTTTCCTCT 1-11- TtctactatactTtCctCT 629_2 -20.85 30711 1-1-1- 2-2 629 TTCTACTATACTTTCCTCT 1-11- TtctactatactTtcCtCT 629_3 -20.97 30711 1-2-1- 1-2 629 TTCTACTATACTTTCCTCT 1-1-1- TtCtactatactTtcctCT 629_4 -21.06 30711 9-1-4-2 629 TTCTACTATACTTTCCTCT 1-1-1- TtCtactatactttCctCT 629_5 -21.53 30711 11-1-2- 2 629 TTCTACTATACTTTCCTCT 1-3-1- TtctActatactttCctCT 629_6 -20.74 30711 9-1-2-2 629 TTCTACTATACTTTCCTCT 1-4-1- TtctaCtatactttCctCT 629_7 -21.54 30711 8-1-2-2 629 TTCTACTATACTTTCCTCT 1-13- TtctactatactttCctCT 629_8 -20.55 30711 1-2-2 629 TTCTACTATACTTTCCTCT 1-1-1- TtCtactatactttcCtCT 629_9 -21.65 30711 12-1-1- 2 629 TTCTACTATACTTTCCTCT 1-3-1- TtctActatactttcCtCT 629_10 -20.86 30711 10-1-1- 2 629 TTCTACTATACTTTCCTCT 1-14- TtctactatactttcCtCT 629_11 -20.67 30711 1-1-2 629 TTCTACTATACTTTCCTCT 1-1-1- TtCtActatactTtCctCT 629_12 -22.02 30711 1-1-7- 1-1-1- 2-2 629 TTCTACTATACTTTCCTCT 1-1-1- TtCtaCtatactttCctCT 629_13 -22.52 30711 2-1-8- 1-2-2 629 TTCTACTATACTTTCCTCT 1-3-2- TtctACtatactttCctCT 629_14 -22.14 30711 8-1-2-2 629 TTCTACTATACTTTCCTCT 1-1-1- TtCtActatactttcCtCT 629_15 -21.84 30711 1-1-10- 1-1-2 629 TTCTACTATACTTTCCTCT 1-1-1- TtCtaCtatactttcCtCT 629_16 -22.64 30711 2-1-9- 1-1-2 630 GTTCTACTATACTTTCCTC 1-12- GttctactatactTtCcTC 630_1 -20.78 30712 1-1-1- 1-2 630 GTTCTACTATACTTTCCTC 1-4-1- GttctActatactttCcTC 630_2 -20.67 30712 9-1-1-2 630 GTTCTACTATACTTTCCTC 1-14- GttctactatactttCcTC 630_3 -20.48 30712 1-1-2 631 GTTCTACTATACTTTCCT 1-2-1- GttCtActatactTtcCT 631_1 -20.25 30713 1-1-7- 1-2-2 631 GTTCTACTATACTTTCCT 1-2-1- GttCtactatactTtcCT 631_2 -20.06 30713 9-1-2-2 631 GTTCTACTATACTTTCCT 1-2-1- GttCtactatactttCCT 631_3 -22.13 30713 11-3 631 GTTCTACTATACTTTCCT 1-4-1- GttctActatactttCCT 631_4 -21.34 30713 9-3 631 GTTCTACTATACTTTCCT 1-14-3 GttctactatactttCCT 631_5 -21.15 30713 631 GTTCTACTATACTTTCCT 2-1-1- GTtCtActatactttcCT 631_6 -21.50 30713 1-1-10- 2 631 GTTCTACTATACTTTCCT 2-1-1- GTtCtactatactttcCT 631_7 -21.30 30713 12-2 631 GTTCTACTATACTTTCCT 1-2-1- GttCtActatactttcCT 631_8 -19.95 30713 1-1-10- 2 631 GTTCTACTATACTTTCCT 1-2-1- GttCtactatactttcCT 631_9 -19.76 30713 12-2 631 GTTCTACTATACTTTCCT 1-15-2 GttctactatactttcCT 631_10 -18.78 30713 631 GTTCTACTATACTTTCCT 1-2-1- GttCtactatactTtCCT 631_11 -22.43 30713 9-1-1-3 631 GTTCTACTATACTTTCCT 2-1-1- GTtCtActatactTtcCT 631_12 -21.80 30713 1-1-7- 1-2-2 631 GTTCTACTATACTTTCCT 1-2-2- GttCTactatactTtcCT 631_13 -21.68 30713 8-1-2-2 631 GTTCTACTATACTTTCCT 1-2-1- GttCtActatactttCCT 631_14 -22.32 30713 1-1-9-3 631 GTTCTACTATACTTTCCT 1-2-3- GttCTActatactttcCT 631_15 -22.60 30713 10-2 632 AGTTCTACTATACTTTCC 1-12- AgttctactatacTttCC 632_1 -19.37 30714 1-2-2 632 AGTTCTACTATACTTTCC 1-13- AgttctactatactTtCC 632_2 -19.16 30714 1-1-2 632 AGTTCTACTATACTTTCC 1-1-1- AgTtctactatactttCC 632_3 -19.51 30714 13-2 632 AGTTCTACTATACTTTCC 1-15-2 AgttctactatactttCC 632_4 -18.86 30714 632 AGTTCTACTATACTTTCC 1-1-1- AgTtctactatacTttCC 632_5 -20.03 30714 10-1-2- 2 632 AGTTCTACTATACTTTCC 1-4-1- AgttcTactatacTttCC 632_6 -20.31 30714 7-1-2-2 632 AGTTCTACTATACTTTCC 2-14-2 AGttctactatactttCC 632_7 -20.26 30714 632 AGTTCTACTATACTTTCC 1-2-1- AgtTctactatactttCC 632_8 -19.23 30714 12-2 632 AGTTCTACTATACTTTCC 1-4-1- AgttcTactatactttCC 632_9 -19.80 30714 10-2 632 AGTTCTACTATACTTTCC 2-10-1- AGttctactataCtttCC 632_10 -21.25 30714 3-2 632 AGTTCTACTATACTTTCC 1-4-1- AgttcTactataCtttCC 632_11 -20.79 30714 6-1-3-2 632 AGTTCTACTATACTTTCC 1-4-1- AgttcTactatacTTtCC 632_12 -21.13 30714 7-2-1-2 632 AGTTCTACTATACTTTCC 1-1-1- AgTtctactatactTtCC 632_13 -19.82 30714 11-1-1- 2 632 AGTTCTACTATACTTTCC 1-3-1- AgttCtactatactttCC 632_14 -19.83 30714 11-2 633 CAACATTATTAACCACCTTA 1-13- CaacattattaaccACCtTA 633_1 -22.44 33376 3-1-2 633 CAACATTATTAACCACCTTA 4-10- CAACattattaaccAccTTA 633_2 -22.98 33376 1-2-3 633 CAACATTATTAACCACCTTA 2-2-1- CAacAttattaaccaCcTTA 633_3 -21.97 33376 10-1-1- 3 633 CAACATTATTAACCACCTTA 1-4-2- CaacaTTattaaccaCctTA 633_4 -21.08 33376 8-1-2-2 633 CAACATTATTAACCACCTTA 1-1-2- CaACattattaaccaCctTA 633_5 -20.90 33376 11-1-2- 2 633 CAACATTATTAACCACCTTA 1-2-2- CaaCAttattaaccacctTA 633_6 -20.76 33376 13-2 633 CAACATTATTAACCACCTTA 1-1-1- CaAcAttattaaccacCtTA 633_7 -19.97 33376 1-1-11- 1-1-2 633 CAACATTATTAACCACCTTA 1-15-4 CaacattattaaccacCTTA 633_8 -21.21 33376 633 CAACATTATTAACCACCTTA 2-4-1- CAacatTattaaccacctTA 633_9 -20.83 33376 11-2 634 CAACATTATTAACCACCTT 2-10- CAacattattaaCCaccTT 634_1 -21.86 33377 2-3-2 634 CAACATTATTAACCACCTT 1-14-4 CaacattattaaccaCCTT 634_2 -21.36 3337 634 CAACATTATTAACCACCTT 1-1-1- CaAcattattaaccAcCTT 634_3 -19.54 33377 11-1-1- 3 634 CAACATTATTAACCACCTT 3-1-1- CAAcAttattaaccacCTT 634_4 -21.13 33377 11-3 634 CAACATTATTAACCACCTT 3-11- CAAcattattaaccACcTT 634_5 -20.84 33377 2-1-2 634 CAACATTATTAACCACCTT 2-1-2- CAaCAttattaaccAcCTT 634_6 -22.76 33377 9-1-1-3 634 CAACATTATTAACCACCTT 2-1-2- CAaCAttattaaccaCcTT 634_7 -21.83 33377 10-1-1- 2 634 CAACATTATTAACCACCTT 1-1-2- CaACattattaaccaCcTT 634_8 -19.70 33377 11-1-1- 2 634 CAACATTATTAACCACCTT 1-2-1- CaaCattattaaccacCTT 634_9 -19.66 33377 12-3 635 GCAACATTATTAACCACCT 1-1-1- GcAacAttattaACcacCT 635_1 -21.56 33378 2-1-6- 2-3-2 635 GCAACATTATTAACCACCT 1-1-2- GcAAcAttattaAccAcCT 635_2 -21.14 33378 1-1-6- 1-2-1- 1-2 635 GCAACATTATTAACCACCT 1-11- GcaacattattaACcAcCT 635_3 -21.59 33378 2-1-1- 1-2 635 GCAACATTATTAACCACCT 1-4-1- GcaacAttattaAccaCCT 635_4 -22.69 33378 6-1-3-3 635 GCAACATTATTAACCACCT 1-1-1- GcAaCattattaAccacCT 635_5 -21.01 33378 1-1-7- 1-4-2 635 GCAACATTATTAACCACCT 1-11- GcaacattattaAcCacCT 635_6 -20.83 33378 1-1-1- 2-2 635 GCAACATTATTAACCACCT 2-3-1- GCaacAttattaAccacCT 635_7 -22.63 33378 6-1-4-2 635 GCAACATTATTAACCACCT 1-1-1- GcAacattattaaccAcCT 635_8 -20.05 33378 12-1-1- 2 635 GCAACATTATTAACCACCT 1-2-1- GcaAcAttattaaccacCT 635_9 -20.30 33378 1-1-11- 2 636 AGCAACATTATTAACCACC 1-2-1- AgcAacattattaACCACC 636_1 -22.13 33379 9-2-1-3 636 AGCAACATTATTAACCACC 1-11- AgcaacattattAaCcaCC 636_2 -20.80 33379 1-1-1- 2-2 636 AGCAACATTATTAACCACC 1-4-1- AgcaaCattattAAccaCC 636_3 -21.32 33379 6-2-3-2 636 AGCAACATTATTAACCACC 1-2-2- AgcAAcattattAacCaCC 636_4 -21.29 33379 7-1-2- 1-1-2 636 AGCAACATTATTAACCACC 2-11- AGcaacattattaAccaCC 636_5 -21.75 33379 1-3-2 636 AGCAACATTATTAACCACC 1-1-1- AgCaAcattattaAccACC 636_6 -22.16 33379 1-1-8- 1-2-3 636 AGCAACATTATTAACCACC 1-2-1- AgcAaCattattAaccACC 636_7 -21.33 33379 1-1-6- 1-3-3 636 AGCAACATTATTAACCACC 2-1-2- AGcAAcattattaaccaCC 636_8 -22.02 33379 12-2 636 AGCAACATTATTAACCACC 1-15-3 AgcaacattattaaccACC 636_9 -20.45 33379 637 AGCAACATTATTAACCAC 2-1-1- AGcAacattattaACCAC 637_1 -21.97 33380 9-5 637 AGCAACATTATTAACCAC 1-3-1- AgcaAcattattAACCAC 637_2 -21.20 33380 7-6 637 AGCAACATTATTAACCAC 2-10- AGcaacattattAAcCAC 637_3 -19.42 33380 2-1-3 637 AGCAACATTATTAACCAC 1-2-1- AgcAacattattAaCCAC 637_4 -19.84 33380 8-1-1-4 637 AGCAACATTATTAACCAC 3-9-3- AGCaacattattAACCAC 637_5 -20.94 33380 1-2 637 AGCAACATTATTAACCAC 1-1-3- AgCAAcattattAACcAC 637_6 -20.15 33380 7-3-1-2 637 AGCAACATTATTAACCAC 1-1-3- AgCAAcattattAAcCAC 637_7 -20.96 33380 7-2-1-3 637 AGCAACATTATTAACCAC 5-7-1- AGCAAcattattAaccAC 637_8 -21.24 33380 3-2 637 AGCAACATTATTAACCAC 3-1-1- AGCaAcattattaAccAC 637_9 -19.86 33380 8-1-2-2 638 GTTTCCATCTACTATTAAT 1-3-1- GtttCcatctacTaTtAAT 638_1 -19.59 39806 7-1-1- 1-1-3 638 GTTTCCATCTACTATTAAT 1-1-1- GtTtccatctacTAttaAT 638_2 -19.50 39806 9-2-3-2 638 GTTTCCATCTACTATTAAT 1-4-1- GtttcCatctacTAttAAT 638_3 -20.09 39806 6-2-2-3 638 GTTTCCATCTACTATTAAT 1-3-1- GtttCcatctactAttAAT 638_4 -18.3 39806 8-1-2-3 638 GTTTCCATCTACTATTAAT 3-1-1- GTTtCcatctactAttaAT 638_5 -20.35 39806 8-1-3-2 638 GTTTCCATCTACTATTAAT 1-2-2- GttTCcatctactattaAT 638_6 -18.88 39806 12-2 638 GTTTCCATCTACTATTAAT 1-1-1- GtTtccatctactaTtAAT 638_7 -18.18 39806 11-1-1- 3 638 GTTTCCATCTACTATTAAT 2-2-1- GTttCcatctactatTaAT 638_8 -20.16 39806 10-1-1- 2 638 GTTTCCATCTACTATTAAT 1_1-1- GtTtCCatctactattAAT 638_9 -20.69 39806 1-2-10- 3 638 GTTTCCATCTACTATTAAT 2-2-1- GTttCcatctacTattAAT 638_10 -20.69 39806 7-1-3-3 638 GTTTCCATCTACTATTAAT 1-1-1- GtTtccatctactATtAAT 638_11 -19.08 39806 10-2-1- 3 638 GTTTCCATCTACTATTAAT 1-3-1- GtttCcatctactAtTaAT 638_12 -18.72 39806 8-1-1- 1-1-2 638 GTTTCCATCTACTATTAAT 1-2-3- GttTCCatctactAttAAT 638_13 -21.47 39806 7-1-2-3 638 GTTTCCATCTACTATTAAT 1-1-1- GtTtCCatctactattaAT 638_14 -20.37 39806 1-2-11- 2 639 GTTTCCATCTACTATTAA 1-11- GtttccatctacTAtTAA 639_1 -19.21 39807 2-1-3 639 GTTTCCATCTACTATTAA 1-3-1- GtttCcatctacTaTTAA 639_2 -19.80 39807 7-1-1-4 639 GTTTCCATCTACTATTAA 3-1-1- GTTtCcatctacTAttAA 639_3 -20.57 39807 7-2-2-2 639 GTTTCCATCTACTATTAA 2-2-1- GTttCcatctacTaTtAA 639_4 -19.07 39807 7-1-1- 1-1-2 639 GTTTCCATCTACTATTAA 1-3-2- GtttCCatctactATtAA 639_5 -19.67 39807 7-2-1-2 639 GTTTCCATCTACTATTAA 3-2-1- GTTtcCatctacTattAA 639_6 -19.25 39807 6-1-3-2 639 GTTTCCATCTACTATTAA 1-1-3- GtTTCcatctactAttAA 639_7 -18.04 39807 8-1-2-2 639 GTTTCCATCTACTATTAA 1-1-1- GtTtCCatctactattAA 639_8 -18.62 39807 1-2-10- 2 639 GTTTCCATCTACTATTAA 3-1-1- GTTtCcatctactaTTAA 639_9 -21.21 39807 9-4 639 GTTTCCATCTACTATTAA 1-3-2- GtttCCatctacTAttAA 639_10 -20.39 39807 6-2-2-2 639 GTTTCCATCTACTATTAA 1-1-3- GtTTCcatctacTaTtAA 639_11 -19.32 39807 7-1-1- 1-1-2 639 GTTTCCATCTACTATTAA 2-2-1- GTttCcatctacTatTAA 639_12 -20.39 39807 7-1-2-3 639 GTTTCCATCTACTATTAA 2-2-1- GTttCcatctactATtAA 639_13 -19.03 39807 8-2-1-2 639 GTTTCCATCTACTATTAA 1-1-1- GtTtCCatctactaTTAA 639_14 -21.34 39807 1-2-8-4 640 TGTTTCCATCTACTATTA 1-1-1- TgTttccatctactAtTA 640_1 -18.41 39808 11-1-1- 2 640 TGTTTCCATCTACTATTA 1-2-1- TgtTtccatctacTAtTA 640_2 -20.03 39808 9-2-1-2 640 TGTTTCCATCTACTATTA 1-4-1- TgtttCcatctacTatTA 640_3 -19.37 39808 7-1-2-2 640 TGTTTCCATCTACTATTA 1-4-1- TgtttCcatctactATTA 640_4 -20.28 39808 8-4 640 TGTTTCCATCTACTATTA 1-4-1- TgtttCcatctactAtTA 640_5 -18.52 39808 8-1-1-2 640 TGTTTCCATCTACTATTA 1-1-2- TgTTtCcatctactatTA 640_6 -19.89 39808 1-1-10- 2 640 TGTTTCCATCTACTATTA 1-4-1- TgtttCcatctactaTTA 640_7 -19.37 39808 9-3 640 TGTTTCCATCTACTATTA 1-2-1- TgtTtCcatctactatTA 640_8 -18.73 39808 1-1-10- 2 640 TGTTTCCATCTACTATTA 1-4-1- TgtttCcatctactatTA 640_9 -18.42 39808 10-2 640 TGTTTCCATCTACTATTA 1-4-1- TgtttCcatctaCtATTA 640_10 -21.27 39808 6-1-1-4 640 TGTTTCCATCTACTATTA 2-1-1- TGtTtccatctacTAtTA 640_11 -21.24 39808 9-2-1-2 640 TGTTTCCATCTACTATTA 1-3-2- TgttTCcatctactAtTA 640_12 -19.51 39808 8-1-1-2 640 TGTTTCCATCTACTATTA 2-1-1- TGtTtCcatctactatTA 640_13 -19.94 39808 1-1-10- 2 640 TGTTTCCATCTACTATTA 1-1-1- TgTttCcatctactatTA 640_14 -19.08 39808 2-1-10- 2 641 ACTCTGCAATACACCAA 2-1-1- ACtCtgcaatacACCAA 641_1 -19.61 44439 8-2-1-2 641 ACTCTGCAATACACCAA 2-2-1- ACtcTgcaataCaCcAA 641_2 -19.77 44439 6-1-1- 1-1-2 641 ACTCTGCAATACACCAA 1-2-1- ActCtgcaataCaCcAA 641_3 -18.35 44439 7-1-1- 1-1-2 641 ACTCTGCAATACACCAA 2-1-2- ACtCTgcaataCAccAA 641_4 -22.21 44439 6-2-2-2 641 ACTCTGCAATACACCAA 1-3-1- ActcTgcaatacAcCAA 641_5 -19.05 44439 7-1-1-3 641 ACTCTGCAATACACCAA 4-8-1- ACTCtgcaatacAccAA 641_6 -20.30 44439 2-2 641 ACTCTGCAATACACCAA 2-1-2- ACtCTgcaatacacCAA 641_7 -21.96 44439 9-3 641 ACTCTGCAATACACCAA 2-11-4 ACtctgcaatacaCCAA 641_8 -21.68 44439 641 ACTCTGCAATACACCAA 1-1-2- AcTCtgcaatacacCAA 641_9 -20.07 44439 10-3 642 CTGTATACACCATCCCA 1-10- CtgtatacaccAtCcCA 642_1 -21.99 46391 1-1-1- 1-2 642 CTGTATACACCATCCCA 1-10- CtgtatacaccAtccCA 642_2 -21.22 46391 1-3-2 642 CTGTATACACCATCCCA 1-1-1- CtGtatacaccAtccCA 642_3 -21.53 46391 8-1-3-2 642 CTGTATACACCATCCCA 1-2-1- CtgTatacaccAtccCA 642_4 -22.31 46391 7-1-3-2 642 CTGTATACACCATCCCA 1-3-1- CtgtAtacaccAtccCA 642_5 -21.32 46391 6-1-3-2 642 CTGTATACACCATCCCA 1-11- CtgtatacaccaTCcCA 642_6 -23.06 46391 2-1-2 642 CTGTATACACCATCCCA 1-1-1- CtGtAtacaccatCcCA 642_7 -22.35 46391 1-1-8- 1-1-2 642 CTGTATACACCATCCCA 1-1-1- CtGtatacaccatCcCA 642_8 -22.25 46391 10-1-1- 2 642 CTGTATACACCATCCCA 1-2-1- CtgTatacaccatCcCA 642_9 -23.02 46391 9-1-1-2 642 CTGTATACACCATCCCA 1-3-1- CtgtAtacaccatCcCA 642_10 -22.04 46391 8-1-1-2 642 CTGTATACACCATCCCA 1-12- CtgtatacaccatCcCA 642_11 -21.94 46391 1-1-2 642 CTGTATACACCATCCCA 2-2-1- CTgtAtacaccatccCA 642_12 -22.95 46391 10-2 642 CTGTATACACCATCCCA 1-1-1- CtGtAtacaccatccCA 642_13 -21.58 46391 1-1-10- 2 642 CTGTATACACCATCCCA 1-1-1- CtGtatacaccatccCA 642_14 -21.48 46391 12-2 642 CTGTATACACCATCCCA 1-2-2- CtgTAtacaccatccCA 642_15 -23.39 46391 10-2 642 CTGTATACACCATCCCA 1-3-1- CtgtAtacaccatccCA 642_16 -21.27 46391 10-2 642 CTGTATACACCATCCCA 1-14-2 CtgtatacaccatccCA 642_17 -21.17 46391 642 CTGTATACACCATCCCA 1-3-1- CtgtAtacaccATCcCA 642_18 -24.02 46391 6-3-1-2 642 CTGTATACACCATCCCA 1-1-1- CtGtatacaccAtCcCA 642_19 -22.30 46391 8-1-1- 1-1-2 642 CTGTATACACCATCCCA 1-1-3- CtGTAtacaccAtccCA 642_20 -24.64 46391 6-1-3-2 642 CTGTATACACCATCCCA 2-2-1- CTgtAtacaccatCcCA 642_21 -23.72 46391 8-1-1-2 642 CTGTATACACCATCCCA 1-3-1- CtgtAtacaccatcCCA 642_22 -23.55 46391 9-3 643 TCTGTATACACCATCCCA 1-4-1- TctgtAtacaccatCcCA 643_1 -22.94 46391 8-1-1-2 644 TCTGTATACACCATCCC 2-10- TCtgtatacaccAtcCC 644_1 -22.70 46392 1-2-2 644 TCTGTATACACCATCCC 1-11- TctgtatacaccAtcCC 644_2 -21.11 46392 1-2-2 644 TCTGTATACACCATCCC 2-1-1- TCtGtatacaccatcCC 644_3 -22.96 46392 11-2 644 TCTGTATACACCATCCC 2-13-2 TCtgtatacaccatcCC 644_4 -22.65 46392 644 TCTGTATACACCATCCC 3-9-1- TCTgtatacaccAtcCC 644_5 -24.39 46392 2-2 644 TCTGTATACACCATCCC 2-1-1- TCtGtatacaccAtcCC 644_6 -23.01 46392 8-1-2-2 645 TTCTGTATACACCATCCC 1-11- TtctgtatacacCatcCC 645_1 -22.57 46392 1-3-2 645 TTCTGTATACACCATCCC 1-1-1- TtCtgtatacaccAtcCC 645_2 -23.02 46392 10-1-2- 2 645 TTCTGTATACACCATCCC 1-3-1- TtctGtatacaccAtcCC 645_3 -22.36 46392 8-1-2-2 645 TTCTGTATACACCATCCC 1-12- TtctgtatacaccAtcCC 645_4 -22.05 46392 1-2-2 645 TTCTGTATACACCATCCC 1-15-2 TtctgtatacaccatcCC 645_5 -22.00 46392 645 TTCTGTATACACCATCCC 1-4-1- TtctgTatacacCAtcCC 645_6 -25.12 46392 6-2-2-2 645 TTCTGTATACACCATCCC 1-3-1- TtctGtatacaccAtCCC 645_7 -24.73 46392 8-1-1-3 645 TTCTGTATACACCATCCC 3-10-1- TTCtgtatacaccAtcCC 645_8 -24.52 46392 2-2 645 TTCTGTATACACCATCCC 1-1-2- TICTgtatacaccAtcCC 645_9 -24.71 46392 9-1-2-2 645 TTCTGTATACACCATCCC 1-1-1- TtCtGtatacaccAtcCC 645_10 -23.34 46392 1-1-8- 1-2-2 646 TTCTGTATACACCATCC 1-10- TtctgtatacaCcatCC 646_1 -19.96 46393 1-3-2 646 TTCTGTATACACCATCC 1-12-4 TtctgtatacaccATCC 646_2 -21.16 46393 646 TTCTGTATACACCATCC 2-11- TTctgtatacaccAtCC 646_3 -20.11 46393 1-1-2 646 TTCTGTATACACCATCC 1-2-1- TtcTgtatacaccAtCC 646_4 -20.24 46393 9-1-1-2 646 TTCTGTATACACCATCC 1-3-1- TtctGtatacaccAtCC 646_5 -19.54 46393 8-1-1-2 646 TTCTGTATACACCATCC 1-2-1- TtcTgtatacacCatCC 646_6 -20.77 46393 8-1-2-2 646 TTCTGTATACACCATCC 1-12- TtctgtatacaccAtCC 646_7 -19.23 46393 1-1-2 646 TTCTGTATACACCATCC 1-3-1- TtctGtatacacCaTCC 646_8 -21.19 46393 7-1-1-3 646 TTCTGTATACACCATCC 1-1-1- TtCtGtatacaccatCC 646_9 -20.47 46393 1-1-10- 2 646 TTCTGTATACACCATCC 1-1-1- TtCtgtatacaccatCC 646_10 -20.16 46393 12-2 646 TTCTGTATACACCATCC 1-1-1- TtCtgtatacaccaTCC 646_11 -21.28 46393 11-3 646 TTCTGTATACACCATCC 1-3-1- TtctGtatacaccaTCC 646_12 -20.61 46393 9-3 646 TTCTGTATACACCATCC 1-13-3 TtctgtatacaccaTCC 646_13 -20.30 46393 646 TTCTGTATACACCATCC 3-1-1- TTCtGtatacaccatCC 646_14 -21.96 46393 10-2 646 TTCTGTATACACCATCC 3-12-2 TTCtgtatacaccatCC 646_15 -21.65 46393 646 TTCTGTATACACCATCC 1-1-2- TtCTgtatacaccatCC 646_16 -21.84 46393 11-2 646 TTCTGTATACACCATCC 1-2-1- TtcTgtatacaccatCC 646_17 -20.19 46393 11-2 646 TTCTGTATACACCATCC 1-3-1- TtctGtatacaccatCC 646_18 -19.49 46393 10-2 646 TTCTGTATACACCATCC 1-14-2 TtctgtatacaccatCC 646_19 -19.18 46393 646 TTCTGTATACACCATCC 3-8-1- TTCtgtatacaCcatCC 646_20 -22.44 46393 3-2 646 TTCTGTATACACCATCC 1-3-1- TtctGtatacaCcatCC 646_21 -20.27 46393 6-1-3-2 646 TTCTGTATACACCATCC 1-3-1- TtctGtatacacCAtCC 646_22 -21.53 46393 7-2-1-2 646 TTCTGTATACACCATCC 1-1-1- TtCtgtatacacCatCC 646_23 -20.74 46393 9-1-2-2 646 TTCTGTATACACCATCC 1-1-1- TtCtgtatacaccAtCC 646_24 -20.21 46393 10-1-1- 2 647 AGCTTTTAACCAGAGT 2-10-4 AGcttttaaccaGAGT 647_1 -21.73 EX-EX 648 AGCTTTTAACCAGAGTG 2-11-4 AGcttttaaccagAGTG 648_1 -22.27 EX-EX 649 AGCTTTTAACCAGAGTGG 1-14-3 AgcttttaaccagagTGG 649_1 -21.63 EX-EX 650 AGCTTTTAACCAGAGTGGC 1-16-2 AgcttttaaccagagtgGC 650_1 -23.20 EX-EX 651 AGCTTTTAACCAGAGTGGCA 1-17-2 AgcttttaaccagagtggCA 651_1 -24.11 EX-EX 652 CAGCTTTTAACCAGAGT 2-12-3 CAgcttttaaccagAGT 652_1 -21.65 EX-EX 653 CAGCTTTTAACCAGAGTG 3-13-2 CAGcttttaaccagagTG 653_1 -22.27 EX-EX 654 CAGCTTTTAACCAGAGTGG 1-15-3 CagcttttaaccagagTGG 654_1 -22.97 EX-EX 655 CAGCTTTTAACCAGAGTGGC 1-17-2 CagcttttaaccagagtgGC 655_1 -24.53 EX-EX 656 CTTTTAACCAGAGTG 4-7-4 CTTTtaaccagAGTG 656_1 -20.12 EX-EX 657 CTTTTAACCAGAGTGG 4-9-3 CTTTtaaccagagTGG 657_1 -20.92 EX-EX 658 CTTTTAACCAGAGTGGC 4-11-2 CTTTtaaccagagtgGC 658_1 -22.48 EX-EX 659 CTTTTAACCAGAGTGGCA 1-14-3 CttttaaccagagtgGCA 659_1 -22.96 EX-EX 660 CTTTTAACCAGAGTGGCAT 3-13-3 CTTttaaccagagtggCAT 660_1 -24.65 EX-EX 661 CTTTTAACCAGAGTGGCATC 2-16-2 CTtttaaccagagtggcaTC 661_1 -23.19 EX-EX 662 GCTTTTAACCAGAGT 3-9-3 GCTtttaaccagAGT 662_1 -21.02 EX-EX 663 GCTTTTAACCAGAGTG 4-10-2 GCTTttaaccagagTG 663_1 -21.02 EX-EX 664 GCTTTTAACCAGAGTGG 1-12-4 GcttttaaccagaGTGG 664_1 -22.24 EX-EX 665 GCTTTTAACCAGAGTGGC 1-14-3 GcttttaaccagagtGGC 665_1 -23.42 EX-EX 666 GCTTTTAACCAGAGTGGCA 1-16-2 GcttttaaccagagtggCA 666_1 -22.94 EX-EX 667 GCTTTTAACCAGAGTGGCAT 1-16-3 GcttttaaccagagtggCAT 667_1 -25.01 EX-EX 668 TCAGCTTTTAACCAGAGT 2-13-3 TCagcttttaaccagAGT 668_1 -22.18 EX-EX 669 TCAGCTTTTAACCAGAGTG 2-14-3 TCagcttttaaccagaGTG 669_1 -23.15 EX-EX 670 TCAGCTTTTAACCAGAGTGG 2-16-2 TCagcttttaaccagagtGG 670_1 -23.41 EX-EX 671 TTCAGCTTTTAACCAGAGT 2-14-3 TTcagcttttaaccagAGT 671_1 -22.72 EX-EX 672 TTCAGCTTTTAACCAGAGTG 2-15-3 TTcagcttttaaccagaGTG 672_1 -23.69 EX-EX 673 TTTCAGCTTTTAACCAGAGT 2-15-3 TTtcagcttttaaccagAGT 673_1 -23.66 EX-EX 674 TTTTAACCAGAGTGGC 1-11-4 TtttaaccagagTGGC 674_1 -20.81 EX-EX 675 TTTTAACCAGAGTGGCA 3-11-3 TTTtaaccagagtgGCA 675_1 -22.30 EX-EX 676 TTTTAACCAGAGTGGCAT 4-11-3 TTTTaaccagagtggCAT 676_1 -23.21 EX-EX 677 TTTTAACCAGAGTGGCATC 4-13-2 TTTTaaccagagtggcaTC 677_1 -22.57 EX-EX 678 TTTTAACCAGAGTGGCATCC 2-16-2 TTttaaccagagtggcatCC 678_1 -24.58 EX-EX 679 ATCAATATCTTCTCACT 1-1-2- AtCAatatcttCtCaCT 679_1 -19.16 5782 7-1-1- 1-1-2 679 ATCAATATCTTCTCACT 5-6-1- ATCAAtatcttCtcACT 679_2 -21.49 5782 2-3 679 ATCAATATCTTCTCACT 1-1-1- AtCaAtatcttcTCACT 679_3 -20.18 5782 1-1-7-5 679 ATCAATATCTTCTCACT 1-1-3- AtCAAtatcttctCACT 679_4 -20.66 5782 8-4 679 ATCAATATCTTCTCACT 3-10-1- ATCaatatcttctCaCT 679_5 -18.62 5782 1-2 680 TATCAATATCTTCTCACT 2-2-1- TAtcAatatcttCtCaCT 680_1 -19.31 5782 7-1-1- 1-1-2 680 TATCAATATCTTCTCACT 1-1-2- TaTCaatatcttCtCaCT 680_2 -19.89 5782 8-1-1- 1-1-2 680 TATCAATATCTTCTCACT 1-2-3- TatCAAtatcttCtcACT 680_3 -20.66 5782 6-1-2-3 680 TATCAATATCTTCTCACT 1-2-3- TatCAAtatcttcTCaCT 680_4 -20.99 5782 7-2-1-2 680 TATCAATATCTTCTCACT 2-1-1- TAtCaatatcttctCACT 680_5 -20.89 5782 10-4 681 TATCAATATCTTCTCAC 4-7-2- TATCaatatctTCtCAC 681_1 -21.30 5783 1-3 681 TATCAATATCTTCTCAC 1-2-2- TatCAatatctTCtCAC 681_2 -19.73 5783 6-2-1-3 681 TATCAATATCTTCTCAC 2-1-1- TAtCaatatcttCTCAC 681_3 -20.26 5783 8-5 681 TATCAATATCTTCTCAC 1-1-3- TaTCAatatcttCTCAC 681_4 -21.74 5783 7-5 681 TATCAATATCTTCTCAC 5-9-3 TATCAatatcttctCAC 681_5 -20.83 5783 682 TTATCAATATCTTCTCAC 1-1-1- TtAtCAatatctTCtcAC 682_1 -18.32 5783 1-2-6- 2-2-2 682 TTATCAATATCTTCTCAC 1-3-1- TtatCaatatcttCTCAC 682_2 -19.71 5783 8-5 682 TTATCAATATCTTCTCAC 3-10-1- TTAtcaatatcttCtCAC 682_3 -19.53 5783 1-3 682 TTATCAATATCTTCTCAC 2-1-2- TTaTCaatatcttCtCAC 682_4 -20.20 5783 8-1-1-3 682 TTATCAATATCTTCTCAC 1-2-3- TtaTCAatatcttctCAC 682_5 -19.47 5783 9-3 683 TTATCAATATCTTCTCACT 1-1-1- TtAtCaatatcttCtCaCT 683_1 -19.45 5782 1-1-8- 1-1-1- 1-2 683 TTATCAATATCTTCTCACT 1-3-1- TtatCaatatcttCtCaCT 683_2 -19.35 5782 8-1-1- 1-1-2 683 TTATCAATATCTTCTCACT 1-1-1- TtAtCaatatcttCtcACT 683_3 -19.33 5782 1-1-8- 1-2-3 683 TTATCAATATCTTCTCACT 1-1-1- TtAtcAatatcttCtcaCT 683_4 -18.18 5782 2-1-7- 1-3-2 683 TTATCAATATCTTCTCACT 1-1-1- TtAtcAatatcttctCACT 683_5 -19.84 5782 2-1-9-4 684 ACCTTTCTTTAACCCTTT 2-1-1- ACcTttctttaaCCcTTT 684_1 -25.24 8113 8-2-1-3 684 ACCTTTCTTTAACCCTTT 2-10-1- ACctttctttaaCcCtTT 684_2 -22.31 8113 1-1-1-2 684 ACCTTTCTTTAACCCTTT 1-1-1- AcCtttctttaaCcCtTT 684_3 -22.01 8113 9-1-1- 1-1-2 684 ACCTTTCTTTAACCCTTT 1-1-1- AcCtTtctttaaccCtTT 684_4 -21.53 8113 1-1-9- 1-1-2 684 ACCTTTCTTTAACCCTTT 1-1-1- AcCtttctttaaccCtTT 684_5 -21.23 8113 11-1-1- 2 685 TACCTTTCTTTAACCCTTT 1-2-1- TacCtttctttaAcCctTT 685_1 -22.44 8113 8-1-1- 1-2-2 685 TACCTTTCTTTAACCCTTT 1-2-1- TacCtTtctttaaCcCtTT 685_2 -23.32 8113 1-1-7- 1-1-1- 1-2 685 TACCTTTCTTTAACCCTTT 2-1-1- TAcCtttctttaacCcTTT 685_3 -24.28 8113 10-1-1- 3 685 TACCTTTCTTTAACCCTTT 1-1-1- TaCctttctttaaccCtTT 685_4 -22.13 8113 12-1-1- 2 685 TACCTTTCTTTAACCCTTT 1-2-1- TacCtttctttaaccCtTT 685_5 -22.23 8113 11-1-1- 2 686 ATACCTTTCTTTAACCC 1-2-1- AtaCctttcttTaAcCC 686_1 -20.53 8116 7-1-1- 1-1-2 686 ATACCTTTCTTTAACCC 1-3-1- AtacCtttcttTaacCC 686_2 -20.21 8116 6-1-3-2 686 ATACCTTTCTTTAACCC 2-2-1- ATacCtttctttAAcCC 686_3 -21.89 8116 7-2-1-2 686 ATACCTTTCTTTAACCC 1-1-1- AtAcCtttctttaAcCC 686_4 -20.10 8116 1-1-8- 1-1-2 686 ATACCTTTCTTTAACCC 1-2-1- AtaCctttctttaaCCC 686_5 -21.76 8116 10-3 687 ATACCTTTCTTTAACCCTT 1-3-2- AtacCTttctttAacCCTT 687_1 -26.10 8114 6-1-2-4 687 ATACCTTTCTTTAACCCTT 1-1-1- AtAcCtttctttaAcCcTT 687_2 -22.23 8114 1-1-8- 1-1-1- 1-2 687 ATACCTTTCTTTAACCCTT 1-2-1- AtaCctttctttaAcCcTT 687_3 -21.93 8114 9-1-1- 1-1-2 687 ATACCTTTCTTTAACCCTT 1-2-1- AtaCcTttctttaaCCcTT 687_4 -24.41 8114 1-1-8- 2-1-2 687 ATACCTTTCTTTAACCCTT 1-3-1- AtacCtttctttaaccCTT 687_5 -22.51 8114 11-3 688 ATACCTTTCTTTAACCCTTT 1-3-1- AtacCtttctttaAcCctTT 688_1 -22.83 8113 8-1-1- 1-2-2 688 ATACCTTTCTTTAACCCTTT 1-3-1- AtacCtttctttaaCcCtTT 688_2 -23.41 8113 9-1-1- 1-1-2 688 ATACCTTTCTTTAACCCTTT 1-4-2- AtaccTTtctttaaCccTTT 688_3 -23.98 8113 7-1-2-3 688 ATACCTTTCTTTAACCCTTT 1-1-1- AtAcCtttctttaacCcTTT 688_4 -23.63 8113 1-1-10- 1-1-3 688 ATACCTTTCTTTAACCCTTT 1-2-1- AtaCctttctttaaccCtTT 688_5 -22.52 8113 12-1-1- 2 689 ATACCTTTCTTTAACCCT 1-3-2- AtacCTttctttAAccCT 689_1 -22.61 8115 6-2-2-2 689 ATACCTTTCTTTAACCCT 1-1-1- AtAcCTttctttaaCcCT 689_2 -22.85 8115 1-2-8- 1-1-2 689 ATACCTTTCTTTAACCCT 1-2-1- AtaCctttctttaaCcCT 689_3 -21.36 8115 10-1-1- 2 689 ATACCTTTCTTTAACCCT 1-2-3- AtaCCTttctttaaccCT 689_4 -24.26 8115 10-2 689 ATACCTTTCTTTAACCCT 1-3-1- AtacCtttctttaaccCT 689_5 -20.69 8115 11-2 690 TATACCTTTCTTTAACCCT 2-2-1- TAtaCctttctttaaCcCT 690_1 -23.60 8115 10-1-1- 2 690 TATACCTTTCTTTAACCCT 1-4-1- TatacCtttctttaaCcCT 690_2 -22.57 8115 9-1-1-2 690 TATACCTTTCTTTAACCCT 2-3-1- TAtacCtttctttaaccCT 690_3 -22.92 8115 11-2 690 TATACCTTTCTTTAACCCT 1-3-1- TataCctttctttaaccCT 690_4 -21.68 8115 12-2 690 TATACCTTTCTTTAACCCT 1-4-1- TatacCtttctttaaccCT 690_5 -21.79 8115 11-2 691 TTATACCTTTCTTTAAC 4-7-2- TTATacctttcTTtaAC 691_1 -18.49 8118 2-2 691 TTATACCTTTCTTTAAC 3-8-1- TTAtacctttcTtTAAC 691_2 -18.07 8118 1-4 692 TTATACCTTTCTTTAACCC 2-10-1- TTatacctttctTtAacCC 692_1 -21.94 8116 1-1-2-2 692 TTATACCTTTCTTTAACCC 1-1-1- TtAtacctttctTtaacCC 692_2 -20.68 8116 9-1-4-2 692 TTATACCTTTCTTTAACCC 1-4-1- TtataCctttcttTaacCC 692_3 -21.79 8116 7-1-3-2 692 TTATACCTTTCTTTAACCC 1-3-2- TtatACctttctttAAcCC 692_4 -22.39 8116 8-2-1-2 692 TTATACCTTTCTTTAACCC 1-1-1- TtAtaCctttctttaAcCC 692_5 -21.58 8116 2-1-9- 1-1-2 693 TTATACCTTTCTTTAACC 2-3-1- TTataCctttctTtaaCC 693_1 -19.80 8117 6-1-3-2 693 TTATACCTTTCTTTAACC 1-1-1- TtAtACctttctTtaaCC 693_2 -19.25 8117 1-2-6- 1-3-2 693 TTATACCTTTCTTTAACC 1-3-2- TtatACctttcttTAaCC 693_3 -20.74 8117 7-2-1-2 693 TTATACCTTTCTTTAACC 1-1-1- TtAtaCctttcttTaaCC 693_4 -19.08 8117 2-1-7- 1-2-2 693 TTATACCTTTCTTTAACC 1-2-1- TtaTaCctttctttAACC 693_5 -20.26 8117 1-1-8-4 694 TTTATACCTTTCTTTAACC 2-1-1- TTtAtacctttcTTtaaCC 694_1 -20.72 8117 8-2-3-2 694 TTTATACCTTTCTTTAACC 1-4-1- TttatAcctttcTttAACC 694_2 -20.33 8117 6-1-2-4 694 TTTATACCTTTCTTTAACC 2-11-1- TTtatacctttctTtAaCC 694_3 -19.72 8117 1-1-1-2 694 TTTATACCTTTCTTTAACC 1-1-2- TtTAtacctttctTtaaCC 694_4 -20.65 8117 9-1-3-2 694 TTTATACCTTTCTTTAACC 1-3-2- TttaTAcctttctTtaaCC 694_5 -20.88 8117 7-1-3-2 695 TTTATACCTTTCTTTAAC 3-9-3- TTTatacctttcTTTaAC 695_1 -18.74 8118 1-2 695 TTTATACCTTTCTTTAAC 5-7-2- TTTATacctttcTTtaAC 695_2 -20.31 8118 2-2 695 TTTATACCTTTCTTTAAC 1-1-3- TtTATacctttcTTtaAC 695_3 -18.98 8118 7-2-2-2 695 TTTATACCTTTCTTTAAC 4-8-1- TTTAtacctttcTtTAAC 695_4 -19.89 8118 1-4 695 TTTATACCTTTCTTTAAC 2-3-1- TTtatAcctttctTTAAC 695_5 -18.02 8118 7-5 696 TTTTATACCTTTCTTTAAC 2-3-1- TTttaTacctttCTTtaAC 696_1 -19.79 8118 6-3-2-2 696 TTTTATACCTTTCTTTAAC 1-1-2- TtTTatacctttCTtTaAC 696_2 -19.57 8118 8-2-1- 1-1-2 696 TTTTATACCTTTCTTTAAC 2-1-2- TTtTAtacctttCTttAAC 696_3 -20.28 8118 7-2-2-3 696 TTTTATACCTTTCTTTAAC 3-9-1- TTTtatacctttCtTTAAC 696_4 -20.62 8118 1-5 696 TTTTATACCTTTCTTTAAC 1-1-3- TtTTAtacctttCtTtaAC 696_5 -19.08 8118 7-1-1- 1-2-2 697 TGTACTTTCCTTTACCA 2-9-1- TGtactttcctTtacCA 697_1 -20.68 11462 3-2 697 TGTACTTTCCTTTACCA 1-2-1- TgtActttcctTtacCA 697_2 -19.66 11462 7-1-3-2 697 TGTACTTTCCTTTACCA 1-3-1- TgtaCtttcctTtacCA 697_3 -20.46 11462 6-1-3-2 697 TGTACTTTCCTTTACCA 2-2-1- TGtaCtttcctttAcCA 697_4 -21.56 11462 8-1-1-2 697 TGTACTTTCCTTTACCA 1-3-1- TgtaCtttcctttaCCA 697_5 -22.54 11462 9-3 698 TTATACACCATCATTAT 4-7-3- TTATacaccatCATtAT 698_1 -21.13 11506 1-2 698 TTATACACCATCATTAT 4-7-2- TTATacaccatCAtTAT 698_2 -21.64 11506 1-3 698 TTATACACCATCATTAT 3-8-1- TTAtacaccatCaTTAT 698_3 -19.45 11506 1-4 698 TTATACACCATCATTAT 2-1-2- TTaTAcaccatcATTAT 698_4 -20.61 11506 7-5 698 TTATACACCATCATTAT 5-9-3 TTATAcaccatcatTAT 698_5 -20.74 11506 699 TTATACACCATCATTATA 3-2-1- TTAtaCaccatcATtaTA 699_1 -19.38 11505 6-2-2-2 699 TTATACACCATCATTATA 1-2-3- TtaTACaccatcAtTATA 699_2 -20.93 11505 6-1-1-4 699 TTATACACCATCATTATA 4-1-1- TTATaCaccatcaTTaTA 699_3 -21.44 11505 7-2-1-2 699 TTATACACCATCATTATA 2-1-2- TTaTAcaccatcaTtATA 699_4 -19.71 11505 8-1-1-3 699 TTATACACCATCATTATA 3-2-1- TTAtaCaccatcatTATA 699_5 -20.75 11505 8-4 700 TTTATACACCATCATTAT 2-1-2- TTtATacaccatCATtAT 700_1 -20.67 11506 7-3-1-2 700 TTTATACACCATCATTAT 3-1-1- TTTaTacaccatCAtTAT 700_2 -21.52 11506 7-2-1-3 700 TTTATACACCATCATTAT 1-3-2- TttaTAcaccatCAtTAT 700_3 -20.70 11506 6-2-1-3 700 TTTATACACCATCATTAT 1-1-3- TtTATacaccatcAtTAT 700_4 -20.05 11506 8-1-1-3 700 TTTATACACCATCATTAT 3-1-1- TTTaTacaccatcaTTAT 700_5 -20.34 11506 9-4 701 TTTATACACCATCATTATA 4-8-1- TTTAtacaccatCaTTaTA 701_1 -21.57 11505 1-2-1-2 701 TTTATACACCATCATTATA 2-2-1- TTtaTacaccatCatTATA 701_2 -21.05 11505 7-1-2-4 701 TTTATACACCATCATTATA 1-1-1- TtTaTacaccatcATtATA 701_3 -19.83 11505 1-1-8- 2-1-3 701 TTTATACACCATCATTATA 2-2-2- TTtaTAcaccatcATtaTA 701_4 -20.24 11505 7-2-2-2 701 TTTATACACCATCATTATA 1-1-3- TtTATacaccatcatTaTA 701_5 -20.30 11505 10-1-1- 2 702 ATTTATACACCATCATTAT 1-1-1- AtTta_TacaccatCATtAT 702_1 -20.07 11506 2-1-7- 3-1-2 702 ATTTATACACCATCATTAT 1-1-2- AtTTaTacaccatCAttAT 702_2 -20.07 11506 1-1-7- 2-2-2 702 ATTTATACACCATCATTAT 2-1-2- ATtTAtacaccatCaTtAT 702_3 -19.74 11506 8-1-1- 1-1-2 702 ATTTATACACCATCATTAT 2-3-1- ATttaTacaccatCatTAT 702_4 -20.07 11506 7-1-2-3 702 ATTTATACACCATCATTAT 1-1-1- AtTtAtacaccatcaTTAT 702_5 -18.64 11506 1-1-10- 4 703 ATTTATACACCATCATTATA 1-4-1- AtttaTacaccatCatTATA 703_1 -21.05 11505 7-1-2-4 703 ATTTATACACCATCATTATA 2-1-1- ATtTatAcaccatcATtaTA 703_2 -20.32 11505 2-1-7- 2-2-2 703 ATTTATACACCATCATTATA 1-1-1- AtTtaTacaccatcAtTaTA 703_3 -18.80 11505 2-1-8- 1-1-1- 1-2 703 ATTTATACACCATCATTATA 1-2-3- AttTATacaccatcAtTaTA 703_4 -21.17 11505 8-1-1- 1-1-2 703 ATTTATACACCATCATTATA 3-1-1- ATTtAtacaccatcAttATA 703_5 -19.97 11505 9-1-2-3 704 TATTTATACACCATCATTA 1-2-3- TatTTAtacaccATcatTA 704_1 -20.37 11507 6-2-3-2 704 TATTTATACACCATCATTA 4-8-1- TATTtatacaccAtCAtTA 704_2 -21.70 11507 1-2-1-2 704 TATTTATACACCATCATTA 1-1-1- TaTtTatacaccAtCaTTA 704_3 -19.16 11507 1-1-7- 1-1-1- 1-3 704 TATTTATACACCATCATTA 2-2-1- TAttTatacaccaTCatTA 704_4 -19.98 11507 8-2-2-2 704 TATTTATACACCATCATTA 2-2-1- TAttTatacaccatcATTA 704_5 -19.99 11507 10-4 705 TATTTATACACCATCATTAT 2-2-1- TAttTaTacaccatCAttAT 705_1 -21.49 11506 1-1-7- 2-2-2 705 TATTTATACACCATCATTAT 2-1-1- TAtTtatacaccatCaTTAT 705_2 -21.44 11506 10-1-1- 4 705 TATTTATACACCATCATTAT 1-1-1- TaTttAtacaccatCaTtAT 705_3 -18.27 11506 2-1-8- 1-1-1- 1-2 705 TATTTATACACCATCATTAT 2-1-2- TAtTTatacaccatCattAT 705_4 -19.97 11506 9-1-3-2 705 TATTTATACACCATCATTAT 1-2-3- TatTTAtacaccatcAtTAT 705_5 -21.11 11506 9-1-1-3 706 TTATTTATACACCATCATTA 2-3-1- TTattTatacaccAtCaTTA 706_1 -20.54 11507 7-1-1- 1-1-3 706 TTATTTATACACCATCATTA 1-1-2- TtATtTatacaccAtcATTA 706_2 -20.84 11507 1-1-7- 1-2-4 706 TTATTTATACACCATCATTA 1-1-1- TtAttTatacaccaTCatTA 706_3 -19.52 11507 2-1-8- 2-2-2 706 TTATTTATACACCATCATTA 1-2-3- TtaTTTatacaccaTcAtTA 706_4 -19.96 11507 8-1-1- 1-1-2 706 TTATTTATACACCATCATTA 3-1-1- TTAtTtatacaccatcAtTA 706_5 -19.63 11507 11-1-1- 2 707 ATTATTTATACACCATCAT 2-2-2- ATtaTTtatacaCCAtcAT 707_1 -22.41 11509 6-3-2-2 707 ATTATTTATACACCATCAT 2-3-1- ATtatTtatacaCcaTCAT 707_2 -21.02 11509 6-1-2-4 707 ATTATTTATACACCATCAT 1-1-1- AtTaTttatacacCATCAT 707_3 -20.01 11509 1-1-8- 3-1-2 707 ATTATTTATACACCATCAT 1-1-2- AtTAtTtatacacCatCAT 707_4 -20.30 11509 1-1-7- 1-2-3 707 ATTATTTATACACCATCAT 2-1-2- ATtATttatacaccAtCAT 707_5 -20.20 11509 9-1-1-3 708 ATTATTTATACACCATCA 2-2-2- ATtaTTtatacaCCatCA 708_1 -20.96 11510 6-2-2-2 708 ATTATTTATACACCATCA 3-1-1- ATTaTttatacaCcATCA 708_2 -21.19 11510 7-1-1-4 708 ATTATTTATACACCATCA 1-1-3- AtTATttatacaCcatCA 708_3 -19.39 11510 7-1-3-2 708 ATTATTTATACACCATCA 1-1-1- AtTatTtatacacCAtCA 708_4 -18.57 11510 2-1-7- 2-1-2 708 ATTATTTATACACCATCA 2-1-2- ATtATttatacacCaTCA 708_5 -19.79 11510 8-1-1-3 709 ATTATTTATACACCATCATT 1-2-3- AttATTtatacacCaTCaTT 709_1 -20.97 11508 7-1-1- 2-1-2 709 ATTATTTATACACCATCATT 1-1-1- AtTatTTatacacCatcaTT 709_2 -19.29 11508 2-2-6- 1-4-2 709 ATTATTTATACACCATCATT 1-1-1- AtTatTtatacaccATcATT 709_3 -19.70 11508 2-1-8- 2-1-3 709 ATTATTTATACACCATCATT 3-1-1- ATTaTttatacaccAtCaTT 709_4 -20.09 11508 9-1-1- 1-1-2 709 ATTATTTATACACCATCATT 2-1-2- ATtATtTatacaccAtcATT 709_5 -20.67 11508 1-1-7- 1-2-3 710 ATTATTTATACACCATC 5-6-3- ATTATttatacACCaTC 710_1 -21.70 11511 1-2 710 ATTATTTATACACCATC 5-6-2- ATTATttatacACcATC 710_2 -20.38 11511 1-3 710 ATTATTTATACACCATC 2-2-1- ATtaTttatacaCCATC 710_3 -20.25 11511 7-5 710 ATTATTTATACACCATC 1-1-2- AtTAtttatacaCCATC 710_4 -20.42 11511 8-5 710 ATTATTTATACACCATC 5-8-4 ATTATttatacacCATC 710_5 -21.04 11511 711 AATTATTTATACACCATC 2-2-2- AAttATttatacACCaTC 711_1 -18.93 11511 6-3-1-2 711 AATTATTTATACACCATC 2-1-3- AAtTATttatacAcCATC 711_2 -20.18 11511 6-1-1-4 711 AATTATTTATACACCATC 4-1-1- AATTaTttatacaCCATC 711_3 -22.24 11511 7-5 711 AATTATTTATACACCATC 2-1-2- AAtTAtttatacaCCATC 711_4 -21.17 11511 8-5 711 AATTATTTATACACCATC 1-1-4- AaTTATttatacaCCaTC 711_5 -20.58 11511 7-2-1-2 712 AATTATTTATACACCATCA 1-2-1- AatTaTttatacACCatCA 712_1 -20.42 11510 1-1-6- 3-2-2 712 AATTATTTATACACCATCA 2-2-1- AAttAtttatacAcCAtCA 712_2 -18.54 11510 7-1-1- 2-1-2 712 AATTATTTATACACCATCA 1-1-3- AaTTAtttatacAccATCA 712_3 -20.67 11510 7-1-2-4 712 AATTATTTATACACCATCA 2-1-2- AAtTAtttatacaCCaTCA 712_4 -22.20 11510 8-2-1-3 712 AATTATTTATACACCATCA 3-1-1- AATtAtttatacaCcaTCA 712_5 -19.50 11510 8-1-2-3 713 AAATTATTTATACACCATC 3-2-1- AAAttAtttataCACcATC 713_1 -19.21 11511 6-3-1-3 713 AAATTATTTATACACCATC 1-2-3- AaaTTAtttataCACcaTC 713_2 -20.01 11511 6-3-2-2 713 AAATTATTTATACACCATC 1-1-3- AaATTatttataCAcCATC 713_3 -21.68 11511 7-2-1-4 713 AAATTATTTATACACCATC 2-1-2- AAaTTatttataCaCCaTC 713_4 -19.63 11511 7-1-1- 2-1-2 713 AAATTATTTATACACCATC 1-1-2- AaATtAtttatacaCCATC 713_5 -20.67 11511 1-1-8-5 714 AAATTATTTATACACCAT 1-1-4- AaATTAtttataCAcCAT 714_1 -20.31 11512 6-2-1-3 714 AAATTATTTATACACCAT 2-2-2- AAatTAtttataCaCCAT 714_2 -19.59 11512 6-1-1-4 714 AAATTATTTATACACCAT 1-1-3- AaATTatttataCaCCAT 714_3 -20.00 11512 7-1-1-4 714 AAATTATTTATACACCAT 4-9-5 AAATtatttatacACCAT 714_4 -19.36 11512 714 AAATTATTTATACACCAT 3-1-2- AAAtTAtttatacACCAT 714_5 -19.98 11512 7-5 715 AAAATTATTTATACACCAT 2-1-2- AAaATtatttatACAcCAT 715_1 -19.29 11512 7-3-1-3 715 AAAATTATTTATACACCAT 1-3-2- AaaaTTatttatACaCCAT 715_2 -19.68 11512 6-2-1-4 715 AAAATTATTTATACACCAT 3-2-1- AAAatTatttatAcACCAT 715_3 -19.27 11512 6-1-1-5 715 AAAATTATTTATACACCAT 1-1-4- AaAATTatttataCaCCAT 715_4 -20.75 11512 7-1-1-4 715 AAAATTATTTATACACCAT 2-1-2- AAaATtatttatacACCAT 715_5 -19.38 11512 9-5 716 TAAAATTATTTATACACC 2-1-3- TAaAATtatttaTACaCC 716_1 -18.88 11514 6-3-1-2 716 TAAAATTATTTATACACC 3-1-2- TAAaATtatttatACACC 716_2 -18.95 11514 7-5 716 TAAAATTATTTATACACC 1-1-4- TaAAATtatttatACACC 716_3 -18.33 11514 7-5 716 TAAAATTATTTATACACC 3-1-2- TAAaATtatttataCACC 716_4 -18.35 11514 8-4 716 TAAAATTATTTATACACC 2-1-3- TAaAATtatttataCACC 716_5 -18.35 11514 8-4 717 GTAAAATTATTTATACACC 2-1-3- GTaAAAttatttATACaCC 717_1 -21.68 11514 6-4-1-2 717 GTAAAATTATTTATACACC 3-2-1- GTAaaAttatttATacACC 717_2 -20.00 11514 6-2-2-3 717 GTAAAATTATTTATACACC 3-1-2- GTAaAAttatttaTAcACC 717_3 -20.86 11514 7-2-1-3 717 GTAAAATTATTTATACACC 2-1-3- GTaAAAttatttaTaCACC 717_4 -21.11 11514 7-1-1-4 717 GTAAAATTATTTATACACC 4-1-1- GTAAaAttatttatACACC 717_5 -21.46 11514 8-5 718 GTAAAATTATTTATACAC 4-1-1- GTAAaAttatttaTACAC 718_1 -18.17 11515 7-5 718 GTAAAATTATTTATACAC 3-1-2- GTAaAAttatttaTACAC 718_2 -18.17 11515 7-5 719 GAGTATATTACCTCCA 3-10-3 GAGtatattacctCCA 719_1 -22.56 15162 719 GAGTATATTACCTCCA 2-1-1- GAgTatattacctCCA 719_2 -22.24 15162 9-3 719 GAGTATATTACCTCCA 2-11-3 GAgtatattacctCCA 719_3 -21.15 15162 719 GAGTATATTACCTCCA 1-1-3- GaGTAtattacctCCA 719_4 -22.93 15162 8-3 719 GAGTATATTACCTCCA 5-9-2 GAGTAtattacctcCA 719_5 -23.29 15162 720 CTTTTCTATAATCTCAC 2-2-1- CTttTctataaTCTCAC 720_1 -18.54 30553 6-3-1-2 720 CTTTTCTATAATCTCAC 3-8-2- CTTttctataaTCtCAC 720_2 -19.80 30553 1-3 720 CTTTTCTATAATCTCAC 1-1-3- CtTTTctataaTcTCAC 720_3 -19.40 30553 6-1-1-4 720 CTTTTCTATAATCTCAC 4-8-5 CTTTtctataatCTCAC 720_4 -21.37 30553 720 CTTTTCTATAATCTCAC 1-3-1- CtttTctataatCTCAC 720_5 -18.92 30553 7-5 721 CTTTTCTATAATCTCACA 2-3-1- CTtttCtataatCtCaCA 721_1 -20.17 30552 6-1-1- 1-1-2 721 CTTTTCTATAATCTCACA 1-1-1- CtTtTCtataatCtcACA 721_2 -20.15 30552 1-2-6- 1-2-3 721 CTTTTCTATAATCTCACA 1-2-1- CttTtCtataatcTCaCA 721_3 -19.50 30552 1-1-7- 2-1-2 721 CTTTTCTATAATCTCACA 1-1-3- CtTTTctataatcTcACA 721_4 -19.49 30552 8-1-1-3 721 CTTTTCTATAATCTCACA 3-2-1- CTTttCtataatctCACA 721_5 -21.97 30552 8-4 722 TCTTTTCTATAATCTCACA 1-1-3- TcTTTtctataaTcTcACA 722_1 -21.04 30552 7-1-1- 1-1-3 722 TCTTTTCTATAATCTCACA 1-4-1- TctttTctataaTctCaCA 722_2 -18.81 30552 6-1-2- 1-1-2 722 TCTTTTCTATAATCTCACA 2-2-1- TCttTtctataatCtcACA 722_3 -20.68 30552 8-1-2-3 722 TCTTTTCTATAATCTCACA 2-1-1- TCtTttctataatCtcaCA 722_4 -20.13 30552 9-1-3-2 722 TCTTTTCTATAATCTCACA 2-13-1- TCttttctataatctCaCA 722_5 -19.52 30552 1-2 723 TCTTTTCTATAATCTCAC 2-1-1- TCtTttctataaTCtcAC 723_1 -18.51 30553 8-2-2-2 723 TCTTTTCTATAATCTCAC 3-10-1- TCTtttctataatCtCAC 723_2 -20.36 30553 1-3 723 TCTTTTCTATAATCTCAC 1-2-3- TctTTTctataatCtCAC 723_3 -19.57 30553 7-1-1-3 723 TCTTTTCTATAATCTCAC 2-2-2- TCttTTctataatcTCAC 723_4 -20.57 30553 8-4 723 TCTTTTCTATAATCTCAC 1-1-4- TcTTTTctataatcTCAC 723_5 -20.82 30553 8-4 724 ATCTTTTCTATAATCTCACA 1-1-1- AtCtTttctataatCtCaCA 724_1 -20.93 30552 1-1-9- 1-1-1- 1-2 724 ATCTTTTCTATAATCTCACA 1-1-1- AtCttttctataatCtcACA 724_2 -20.51 30552 11-1-2- 3 724 ATCTTTTCTATAATCTCACA 1-2-1- AtcTtTtctataatCtcACA 724_3 -20.35 30552 1-1-8- 1-2-3 724 ATCTTTTCTATAATCTCACA 1-3-2- AtctTTtctataatCtcaCA 724_4 -20.10 30552 8-1-3-2 724 ATCTTTTCTATAATCTCACA 1-1-1- AtCttTtctataatctCaCA 724_5 -19.95 30552 2-1-10- 1-1-2 725 ATCTTTTCTATAATCTCAC 1-1-1- AtCttttctataAtCtCAC 725_1 -19.62 30553 9-1-1- 1-1-3 725 ATCTTTTCTATAATCTCAC 1-2-2- AtcTTttctataAtCtCAC 725_2 -19.97 30553 7-1-1- 1-1-3 725 ATCTTTTCTATAATCTCAC 1-1-2- AtCTtTtctataaTCtcAC 725_3 -19.83 30553 1-1-7- 2-2-2 725 ATCTTTTCTATAATCTCAC 1-2-1- AtcTtTtctataatcTCAC 725_4 -19.36 30553 1-1-9-4 725 ATCTTTTCTATAATCTCAC 3-13-3 ATCttttctataatctCAC 725_5 -20.25 30553 726 ATCTTTTCTATAATCTCA 1-1-2- AtCTtttctataAtCtCA 726_1 -18.77 30554 8-1-1- 1-1-2 726 ATCTTTTCTATAATCTCA 3-1-1- ATCtTttctataAtcTCA 726_2 -20.03 30554 7-1-2-3 726 ATCTTTTCTATAATCTCA 3-10-2- ATCttttctataaTCtCA 726_3 -20.31 30554 1-2 726 ATCTTTTCTATAATCTCA 1-1-1- AtCtTTtctataaTCtCA 726_4 -19.49 30554 1-2-7- 2-1-2 726 ATCTTTTCTATAATCTCA 1-1-3- AtCTTttctataatCTCA 726_5 -21.14 30554 9-4 727 CATCTTTTCTATAATCTCAC 2-11-1- CAtcttttctataAtCtcAC 727_1 -19.86 30553 1-1-2-2 727 CATCTTTTCTATAATCTCAC 1-1-2- CaTCttttctataAtCtcAC 727_2 -20.49 30553 9-1-1- 1-2-2 727 CATCTTTTCTATAATCTCAC 1-3-1- CatcTtTtctataatCtCAC 727_3 -20.97 30553 1-1-8- 1-1-3 727 CATCTTTTCTATAATCTCAC 1-2-1- CatCtTttctataatCtcAC 727_4 -19.35 30553 1-1-9- 1-2-2 727 CATCTTTTCTATAATCTCAC 2-1-1- CAtCttTtctataatctCAC 727_5 -21.92 30553 2-1-10- 3 728 CATCTTTTCTATAATCTCA 1-3-1- CatcTtttctatAAtCtCA 728_1 -19.26 30554 7-2-1- 1-1-2 728 CATCTTTTCTATAATCTCA 2-3-1- CAtctTttctatAAtcTCA 728_2 -20.74 30554 6-2-2-3 728 CATCTTTTCTATAATCTCA 1-2-1- CatCttttctatAatCtCA 728_3 -19.21 30554 8-1-2- 1-1-2 728 CATCTTTTCTATAATCTCA 2-1-1- CAtCtTttctataatCtCA 728_4 -20.86 30554 1-1-9- 1-1-2 728 CATCTTTTCTATAATCTCA 1-1-2- CaTCttttctataatctCA 728_5 -19.23 30554 13-2 729 TCATCTTTTCTATAATCTCA 1-1-1- TcAtcTtttctatAAtCtCA 729_1 -20.53 30554 2-1-7- 2-1-1- 1-2 729 TCATCTTTTCTATAATCTCA 2-4-1- TCatctTttctatAAtctCA 729_2 -20.57 30554 6-2-3-2 729 TCATCTTTTCTATAATCTCA 2-2-1- TCatCttttctatAatCtCA 729_3 -21.70 30554 8-1-2- 1-1-2 729 TCATCTTTTCTATAATCTCA 3-13-1- TCAtcttttctataatCtCA 729_4 -22.07 30554 1-2 729 TCATCTTTTCTATAATCTCA 3-1-1- TCAtCttttctataatctCA 729_5 -22.07 30554 13-2 730 TCATCTTTTCTATAATCTC 3-2-1- TCAtcTtttctatAAtcTC 730_1 -20.15 30555 7-2-2-2 730 TCATCTTTTCTATAATCTC 3-1-1- TCAtCttttctatAatcTC 730_2 -20.09 30555 8-1-3-2 730 TCATCTTTTCTATAATCTC 2-2-1- TCatCttttctataAtcTC 730_3 -18.83 30555 9-1-2-2 730 TCATCTTTTCTATAATCTC 3-13-3 TCAtcttttctataatCTC 730_4 -20.65 30555 730 TCATCTTTTCTATAATCTC 2-2-2- TCatCTtttctataatCTC 730_5 -21.35 30555 10-3 731 GTCATCTTTTCTATAATC 1-1-1- GtCatCttttctATAaTC 731_1 -19.76 30557 2-1-6- 3-1-2 731 GTCATCTTTTCTATAATC 1-1-1- GtCaTCttttctAtaATC 731_2 -19.19 30557 1-2-6- 1-2-3 731 GTCATCTTTTCTATAATC 4-9-1- GTCAtcttttctaTaaTC 731_3 -20.42 30557 2-2 731 GTCATCTTTTCTATAATC 3-2-1- GTCatCttttctatAATC 731_4 -20.51 30557 8-4 731 GTCATCTTTTCTATAATC 1-1-4- GtCATCttttctataaTC 731_5 -20.23 30557 10-2 732 TGTCATCTTTTCTATAAT 2-1-1- TGtCatcttttcTAtAAT 732_1 -19.36 30558 8-2-1-3 732 TGTCATCTTTTCTATAAT 2-1-2- TGtCAtcttttcTAtaAT 732_2 -20.51 30558 7-2-2-2 732 TGTCATCTTTTCTATAAT 1-1-3- TgTCAtcttttcTataAT 732_3 -19.51 30558 7-1-3-2 732 TGTCATCTTTTCTATAAT 4-10-4 TGTCatcttttctaTAAT 732_4 -21.42 30558 732 TGTCATCTTTTCTATAAT 2-2-1- TGtcAtcttttctaTAAT 732_5 -18.57 30558 9-4 733 ACTTAATTATACTTCCA 5-6-2- ACTTAattataCTtcCA 733_1 -21.55 30664 2-2 733 ACTTAATTATACTTCCA 2-1-2- ACtTAattataCttCCA 733_2 -21.02 30664 6-1-2-3 733 ACTTAATTATACTTCCA 1-2-2- ActTAattatacTTCCA 733_3 -20.65 30664 7-5 733 ACTTAATTATACTTCCA 4-8-1- ACTTaattatacTtCCA 733_4 -21.09 30664 1-3 733 ACTTAATTATACTTCCA 1-1-1- AcTtAattatactTCCA 733_5 -18.37 30664 1-1-8-4 734 CACTTAATTATACTTCC 2-1-2- CAcTTaattatACttCC 734_1 -20.10 30665 6-2-2-2 734 CACTTAATTATACTTCC 5-6-1- CACTTaattatActTCC 734_2 -21.76 30665 2-3 734 CACTTAATTATACTTCC 1-1-1- CaCtTaattataCTtCC 734_3 -19.09 30665 1-1-7- 2-1-2 734 CACTTAATTATACTTCC 1-1-3- CaCTTaattataCtTCC 734_4 -20.59 30665 7-1-1-3 734 CACTTAATTATACTTCC 2-1-2- CAcTTaattatacTTCC 734_5 -20.52 30665 8-4 735 CACTTAATTATACTTCCA 2-2-1- CActTaattataCTtCCA 735_1 -22.96 30664 7-2-1-3 735 CACTTAATTATACTTCCA 2-1-1- CAcTtAattataCttcCA 735_2 -19.31 30664 1-1-6- 1-3-2 735 CACTTAATTATACTTCCA 1-1-3- CaCTTaattatacTtCCA 735_3 -22.43 30664 8-1-1-3 735 CACTTAATTATACTTCCA 1-1-1- CaCtTAattatacTtcCA 735_4 -19.51 30664 1-2-7- 1-2-2 735 CACTTAATTATACTTCCA 2-2-1- CActTaattatactTCCA 735_5 -21.76 30664 9-4 736 ACACTTAATTATACTTCCA 1-1-2- AcACtTaattatACttcCA 736_1 -20.93 30664 1-1-6- 2-3-2 736 ACACTTAATTATACTTCCA 2-2-1- ACacTtaattatAcTtcCA 736_2 -19.38 30664 7-1-1- 1-2-2 736 ACACTTAATTATACTTCCA 1-1-1- AcAcTtaattataCttCCA 736_3 -21.10 30664 1-1-8- 1-2-3 736 ACACTTAATTATACTTCCA 1-1-1- AcActTaattatactTCCA 736_4 -21.31 30664 2-1-9-4 736 ACACTTAATTATACTTCCA 2-2-2- ACacTTaattatacttcCA 736_5 -19.91 30664 11-2 737 ACACTTAATTATACTTCC 1-3-1- AcacTtaattatACtTCC 737_1 -19.24 30665 7-2-1-3 737 ACACTTAATTATACTTCC 1-1-1- AcAcTTaattatACttCC 737_2 -19.64 30665 1-2-6- 2-2-2 737 ACACTTAATTATACTTCC 2-1-2- ACaCTtaattatAcTtCC 737_3 -20.12 30665 7-1-1- 1-1-2 737 ACACTTAATTATACTTCC 3-2-1- ACActTaattatacTTCC 737_4 -21.53 30665 8-4 737 ACACTTAATTATACTTCC 1-1-2- AcACtTaattatactTCC 737_5 -19.40 30665 1-1-9-3 738 ACACTTAATTATACTTC 5-7-5 ACACTtaattatACTTC 738_1 -20.47 30666 738 ACACTTAATTATACTTC 3-1-1- ACAcTtaattatACTTC 738_2 -18.40 30666 7-5 738 ACACTTAATTATACTTC 2-1-2- ACaCTtaattatACTTC 738_3 -18.51 30666 7-5 738 ACACTTAATTATACTTC 5-7-2- ACACTtaattatACtTC 738_4 -18.77 30666 1-2 738 ACACTTAATTATACTTC 5-7-1- ACACTtaattatAcTTC 738_5 -18.40 30666 1-3 738 ACACTTAATTATACTTC 5-8-4 ACACTtaattataCTTC 738_6 -19.88 30666 739 TACACTTAATTATACTTCC 3-2-1- TACacTtaattatACttCC 739_1 -21.57 30665 7-2-2-2 739 TACACTTAATTATACTTCC 1-4-1- TacacTtaattatAcTTCC 739_2 -19.87 30665 7-1-1-4 739 TACACTTAATTATACTTCC 1-2-3- TacACTtaattataCttCC 739_3 -20.88 30665 8-1-2-2 739 TACACTTAATTATACTTCC 4-11-4 TACActtaattatacTTCC 739_4 -23.04 30665 739 TACACTTAATTATACTTCC 2-1-1- TAcAcTtaattatactTCC 739_5 -20.03 30665 1-1-10- 3 740 TACACTTAATTATACTTC 4-1-1- TACAcTtaattatACTTC 740_1 -20.63 30666 7-5 740 TACACTTAATTATACTTC 3-1-2- TACaCTtaattatACTTC 740_2 -20.74 30666 7-5 740 TACACTTAATTATACTTC 2-1-3- TAcACTtaattatACTTC 740_3 -20.21 30666 7-5 740 TACACTTAATTATACTTC 3-1-2- TACaCTtaattataCTTC 740_4 -20.14 30666 8-4 740 TACACTTAATTATACTTC 1-1-4- TaCACTtaattataCTTC 740_5 -20.48 30666 8-4 741 TTACACTTAATTATACTTC 2-1-2- TTaCActtaattATACtTC 741_ -21.41 30666 7-4-1-2 741 TTACACTTAATTATACTTC 5-7-3- TTACActtaattATAcTTC 741_2 -22.67 30666 1-3 741 TTACACTTAATTATACTTC 4-1-1- TTACaCttaattATaCTTC 741_3 -22.54 30666 6-2-1-4 741 TTACACTTAATTATACTTC 2-1-2- TTaCActtaattATaCTTC 741_4 -21.48 30666 7-2-1-4 741 TTACACTTAATTATACTTC 5-7-1- TTACActtaattAtACTTC 741_5 -22.04 30666 1-5 742 TTACACTTAATTATACTT 5-7-3- TTACActtaattATAcTT 742_1 -20.18 30667 1-2 742 TTACACTTAATTATACTT 5-7-2- TTACActtaattATaCTT 742_2 -20.62 30667 1-3 742 TTACACTTAATTATACTT 5-7-1- TTACActtaattAtACTT 742_3 -19.54 30667 1-4 743 TTTACACTTAATTATACTT 4-1-1- TTTAcActtaatTATAcTT 743_1 -21.26 30667 6-4-1-2 743 TTTACACTTAATTATACTT 3-1-2- TTTaCActtaatTATaCTT 743_2 -22.57 30667 6-3-1-3 743 TTTACACTTAATTATACTT 4-8-2- TTTAcacttaatTAtACTT 743_3 -20.48 30667 1-4 743 TTTACACTTAATTATACTT 1-1-4- TtTACActtaatTAtaCTT 743_4 -21.20 30667 6-2-2-3 743 TTTACACTTAATTATACTT 2-2-2- TTtaCActtaatTaTACTT 743_5 -21.02 30667 6-1-1-5 744 TTTACACTTAATTATACT 3-1-2- TTTaCActtaatTATaCT 744_1 -20.75 30668 6-3-1-2 744 TTTACACTTAATTATACT 1-1-4- TtTACActtaatTATaCT 744_2 -21.06 30668 6-3-1-2 744 TTTACACTTAATTATACT 2-1-3- TTtACActtaatTAtACT 744_3 -19.03 30668 6-2-1-3 744 TTTACACTTAATTATACT 4-8-1- TTTAcacttaatTaTACT 744_4 -19.42 30668 1-4 744 TTTACACTTAATTATACT 1-1-1- TtTaCActtaatTaTACT 744_5 -19.12 30668 1-2-6- 1-1-4 745 ATTTACACTTAATTATACT 4-1-1- ATTTaCacttaaTTATaCT 745_1 -22.20 30668 6-4-1-2 745 ATTTACACTTAATTATACT 2-1-3- ATtTACacttaaTTAtACT 745_2 -21.43 30668 6-3-1-3 745 ATTTACACTTAATTATACT 5-7-2- ATTTAcacttaaTTaTACT 745_3 -22.44 30668 1-4 745 ATTTACACTTAATTATACT 1-2-3- AttTACacttaaTTaTACT 745_4 -20.95 30668 6-2-1-4 745 ATTTACACTTAATTATACT 3-1-2- ATTtACacttaaTtATACT 745_5 -20.92 30668 6-1-1-5 746 ATTTACACTTAATTATAC 5-8-5 ATTTAcacttaatTATAC 746_1 -19.94 30669 746 ATTTACACTTAATTATAC 4-1-1- ATTTaCacttaatTATAC 746_2 -19.40 30669 7-5 746 ATTTACACTTAATTATAC 2-1-3- ATtTACacttaatTATAC 746_3 -19.70 30669 7-5 747 AATTTACACTTAATTATAC 3-1-2- AATtTAcacttaATTaTAC 747_1 -19.51 30669 6-3-1-3 747 AATTTACACTTAATTATAC 1-1-4- AaTTTAcacttaATTaTAC 747_2 -19.51 30669 6-3-1-3 747 AATTTACACTTAATTATAC 4-8-2- AATTtacacttaATtATAC 747_3 -18.04 30669 1-4 747 AATTTACACTTAATTATAC 5-7-1- AATTTacacttaAtTATAC 747_4 -19.79 30669 1-5 747 AATTTACACTTAATTATAC 2-1-3- AAtTTAcacttaAtTATAC 747_5 -19.26 30669 6-1-1-5 748 AATTTACACTTAATTATACT 3-2-2- AATttACacttaaTTATaCT 748_1 -21.50 30668 6-4-1-2 748 AATTTACACTTAATTATACT 5-1-1- AATTTaCacttaaTTAtACT 748_2 -21.87 30668 6-3-1-3 748 AATTTACACTTAATTATACT 3-1-3- AATtTACacttaaTTaTACT 748_3 -22.95 30668 6-2-1-4 748 AATTTACACTTAATTATACT 1-1-4- AaTTTAcacttaaTTaTaCT 748_4 -20.23 30668 7-2-1- 1-1-2 748 AATTTACACTTAATTATACT 2-1-2- AAtTTaCacttaaTtATACT 748_5 -20.55 30668 1-1-6- 1-1-5 749 TAATTTACACTTAATTATAC 2-1-4- TAaTTTAcacttaATTAtAC 749_1 -20.98 30669 6-4-1-2 749 TAATTTACACTTAATTATAC 5-8-3- TAATTtacacttaATTaTAC 749_2 -20.60 30669 1-3 749 TAATTTACACTTAATTATAC 2-2-3- TAatTTAcacttaATTaTAC 749_3 -20.80 30669 6-3-1-3 749 TAATTTACACTTAATTATAC 4-1-2- TAATtTAcacttaATtATAC 749_4 -21.41 30669 6-2-1-4 749 TAATTTACACTTAATTATAC 1-1-1- TaAtTTacacttaAtTATAC 749_5 -18.92 30669 1-2-7- 1-1-5 750 TAATTTACACTTAATTAT 5-8-5 TAATTtacacttaATTAT 750_1 -18.27 30671 750 TAATTTACACTTAATTAT 4-1-1- TAATtTacacttaATTAT 750_2 -18.18 30671 7-5 750 TAATTTACACTTAATTAT 2-1-3- TAaTTTacacttaATTAT 750_3 -18.18 30671 7-5 750 TAATTTACACTTAATTAT 1-1-4- TaATTTacacttaATTAT 750_4 -18.16 30671 7-5 751 TAATTTACACTTAATTATA 5-7-4- TAATTtacacttAATTaTA 751_1 -18.87 30670 1-2 751 TAATTTACACTTAATTATA 5-7-2- TAATTtacacttAAtTATA 751_2 -19.05 30670 1-4 751 TAATTTACACTTAATTATA 3-1-2- TAAtTTacacttAAtTATA 751_3 -18.54 30670 6-2-1-4 751 TAATTTACACTTAATTATA 4-1-1- TAATtTacacttAaTTATA 751_4 -19.40 30670 6-1-1-5 751 TAATTTACACTTAATTATA 2-1-3- TAaTTTacacttAaTTATA 751_5 -19.41 30670 6-1-1-5 752 TTAATTTACACTTAATTATA 3-1-3- TTAaTTTacacttAATTaTA 752_1 -20.61 30670 6-4-1-2 752 TTAATTTACACTTAATTATA 5-1-1- TTAATtTacacttAATtATA 752_2 -20.28 30670 6-3-1-3 752 TTAATTTACACTTAATTATA 2-1-4- TTaATTTacacttAAtTATA 752_3 -20.77 30670 6-2-1-4 752 TTAATTTACACTTAATTATA 3-2-2- TTAatTTacacttAaTTATA 752_4 -20.28 30670 6-1-1-5 752 TTAATTTACACTTAATTATA 4-1-1- TTAAtTtacacttaAtTATA 752_5 -18.80 30670 8-1-1-4 753 TTAATTTACACTTAATTAT 4-1-1- TTAAtTtacactTAAtTAT 753_1 -18.65 30671 6-3-1-3 753 TTAATTTACACTTAATTAT 3-1-2- TTAaTTtacactTAaTTAT 753_2 -19.52 30671 6-2-1-4 753 TTAATTTACACTTAATTAT 2-1-2- TTaATttacactTAaTTAT 753_3 -18.68 30671 7-2-1-4 753 TTAATTTACACTTAATTAT 5-7-1- TTAATttacactTaATTAT 753_4 -20.00 30671 1-5 753 TTAATTTACACTTAATTAT 2-1-3- TTaATTtacactTaATTAT 753_5 -19.47 30671 6-1-1-5 754 TTTAATTTACACTTAATTA 3-1-2- TTTaATttacacTTAaTTA 754_1 -19.46 30672 6-3-1-3 754 TTTAATTTACACTTAATTA 5-7-2- TTTAAtttacacTTaATTA 754_2 -19.54 30672 1-4 754 TTTAATTTACACTTAATTA 4-1-1- TTTAaTttacacTTaATTA 754_3 -19.46 30672 6-2-1-4 754 TTTAATTTACACTTAATTA 1-1-1- TtTaATttacacTTaATTA 754_4 -18.11 30672 1-2-6- 2-1-4 754 TTTAATTTACACTTAATTA 1-1-4- TtTAATttacactTAAtTA 754_5 -18.02 30672 7-3-1-2 755 TTTAATTTACACTTAATTAT 4-1-2- TTTAaTTtacactTAAtTAT 755_1 -20.90 30671 6-3-1-3 755 TTTAATTTACACTTAATTAT 3-1-2- TTTaATttacactTAaTTAT 755_2 -20.50 30671 7-2-1-4 755 TTTAATTTACACTTAATTAT 1-1-5- TtTAATTtacactTAaTTAT 755_3 -21.34 30671 6-2-1-4 755 TTTAATTTACACTTAATTAT 5-8-1- TTTAAtttacactTaATTAT 755_4 -20.58 30671 1-5 755 TTTAATTTACACTTAATTAT 2-2-3- TTtaATTtacactTaATTAT 755_5 -20.05 30671 6-1-1-5 756 ATTTAATTTACACTTAATTA 5-1-1- ATTTAaTttacacTTAAtTA 756_1 -21.11 30672 6-4-1-2 756 ATTTAATTTACACTTAATTA 3-2-2- ATTtaATttacacTTAaTTA 756_2 -20.29 30672 6-3-1-3 756 ATTTAATTTACACTTAATTA 4-1-2- ATTTaATttacacTTaATTA 756_3 -21.50 30672 6-2-1-4 756 ATTTAATTTACACTTAATTA 2-1-4- ATtTAATttacacTTaaTTA 756_4 -20.39 30672 6-2-2-3 756 ATTTAATTTACACTTAATTA 2-1-4- ATtTAATttacacttAATTA 756_5 -20.08 30672 8-5 757 ATTTAATTTACACTTAATT 5-7-3- ATTTAatttacaCTTaATT 757_1 -20.52 30673 1-3 757 ATTTAATTTACACTTAATT 4-1-1- ATTTaAtttacacTTaATT 757_2 -18.02 30673 7-2-1-3 757 ATTTAATTTACACTTAATT 2-1-3- ATtTAAtttacacTTaATT 757_3 -18.04 30673 7-2-1-3 757 ATTTAATTTACACTTAATT 4-1-1- ATTTaAtttacactTAATT 757_4 -18.34 30673 8-5 757 ATTTAATTTACACTTAATT 2-1-3- ATtTAAtttacactTAATT 757_5 -18.37 30673 8-5 758 TATTTAATTTACACTTAAT 3-1-2- TATtTAatttacACTTaAT 758_1 -20.16 30674 6-4-1-2 758 TATTTAATTTACACTTAAT 2-1-3- TAtTTAatttacACtTAAT 758_2 -19.37 30674 6-2-1-4 758 TATTTAATTTACACTTAAT 1-1-4- TaTTTAatttacACtTAAT 758_3 -19.19 30674 6-2-1-4 758 TATTTAATTTACACTTAAT 3-1-2- TATtTAatttacAcTTAAT 758_4 -19.44 30674 6-1-1-5 758 TATTTAATTTACACTTAAT 2-1-3- TAtTTAatttacAcTTAAT 758_5 -19.00 30674 6-1-1-5 759 TATTTAATTTACACTTAATT 2-1-4- TAtTTAAtttacaCTTAaTT 759_1 -21.54 30673 6-4-1-2 759 TATTTAATTTACACTTAATT 5-1-1- TATTTaAtttacaCTTaATT 759_2 -21.92 30673 6-3-1-3 759 TATTTAATTTACACTTAATT 4-1-2- TATTtAAtttacacTTAaTT 759_3 -19.35 30673 7-3-1-2 759 TATTTAATTTACACTTAATT 3-1-3- TATtTAAtttacacTTaATT 759_4 -20.28 30673 7-2-1-3 759 TATTTAATTTACACTTAATT 2-1-4- TAtTTAAtttacactTAATT 759_5 -20.16 30673 8-5 760 CTATTTAATTTACACTT 5-6-1- CTATTtaatttAcACTT 760_1 -19.07 30677 1-4 760 CTATTTAATTTACACTT 5-7-5 CTATTtaatttaCACTT 760_2 -20.97 30677 760 CTATTTAATTTACACTT 2-2-1- CTatTtaatttaCACTT 760_3 -18.08 30677 7-5 760 CTATTTAATTTACACTT 5-7-2- CTATTtaatttaCAcTT 760_4 -18.90 30677 1-2 760 CTATTTAATTTACACTT 5-7-1- CTATTtaatttaCaCTT 760_5 -19.01 30677 1-3 761 CTATTTAATTTACACTTAA 2-1-3- CTaTTTaatttaCACTtAA 761_1 -20.98 30675 6-4-1-2 761 CTATTTAATTTACACTTAA 3-1-2- CTAtTTaatttaCACtTAA 761_2 -21.73 30675 6-3-1-3 761 CTATTTAATTTACACTTAA 4-1-1- CTATtTaatttaCAcTTAA 761_3 -21.80 30675 6-2-1-4 761 CTATTTAATTTACACTTAA 5-7-2- CTATTtaatttaCActTAA 761_4 -20.86 30675 2-3 761 CTATTTAATTTACACTTAA 2-1-3- CTaTTTaatttaCaCTTAA 761_5 -21.29 30675 6-1-1-5 762 CTATTTAATTTACACTTA 5-7-3- CTATTtaatttaCACtTA 762_1 -21.50 30676 1-2 762 CTATTTAATTTACACTTA 3-2-1- CTAttTaatttaCACtTA 762_2 -20.17 30676 6-3-1-2 762 CTATTTAATTTACACTTA 3-1-1- CTAtTtaatttaCAcTTA 762_3 -19.37 30676 7-2-1-3 762 CTATTTAATTTACACTTA 2-1-3- CTaTTTaatttaCAcTTA 762_4 -20.43 30676 6-2-1-3 762 CTATTTAATTTACACTTA 2-1-3- CTaTTTaatttaCaCTTA 762_5 -20.54 30676 6-1-1-4 763 CTATTTAATTTACACTTAAT 2-1-4- CTaTTTAatttacACTtaAT 763_1 -21.79 30674 6-3-2-2 763 CTATTTAATTTACACTTAAT 4-1-2- CTATtTAatttacACtTAAT 763_2 -23.29 30674 6-2-1-4 763 CTATTTAATTTACACTTAAT 1-2-4- CtaTTTAatttacAcTTAAT 763_3 -20.68 30674 6-1-1-5 763 CTATTTAATTTACACTTAAT 3-1-3- CTAtTTAatttacAcTTaAT 763_4 -21.14 30674 6-1-1- 2-1-2 763 CTATTTAATTTACACTTAAT 5-1-1- CTATTtAatttacaCTTaAT 763_5 -22.14 30674 7-3-1-2 764 TCTATTTAATTTACACTTA 2-1-3- TCtATTtaatttACACtTA 764_1 -21.94 30676 6-4-1-2 764 TCTATTTAATTTACACTTA 4-1-1- TCTAtTtaatttACAcTTA 764_2 -22.47 30676 6-3-1-3 764 TCTATTTAATTTACACTTA 3-1-2- TCTaTTtaatttaCAcTTA 764_3 -21.69 30676 7-2-1-3 764 TCTATTTAATTTACACTTA 1-1-4- TcTATTtaatttaCActTA 764_4 -20.33 30676 7-2-2-2 764 TCTATTTAATTTACACTTA 3-2-1- TCTatTtaatttaCaCTTA 764_5 -20.85 30676 7-1-1-4 765 TCTATTTAATTTACACTT 3-2-1- TCTatTtaatttACaCTT 765_1 -19.21 30677 6-2-1-3 765 TCTATTTAATTTACACTT 3-1-2- TCTaTTtaatttaCACTT 765_2 -21.53 30677 7-5 765 TCTATTTAATTTACACTT 2-1-3- TCtATTtaatttaCACTT 765_3 -20.81 30677 7-5 765 TCTATTTAATTTACACTT 4-1-1- TCTAtTtaatttaCAcTT 765_4 -19.64 30677 7-2-1-2 765 TCTATTTAATTTACACTT 1-1-4- TcTATTtaatttaCAcTT 765_5 -19.12 30677 7-2-1-2 766 TCTATTTAATTTACACTTAA 2-1-2- TCtATtTaatttaCACttAA 766_1 -20.25 30675 1-1-6- 3-2-2 766 TCTATTTAATTTACACTTAA 4-1-1- TCTAtTtaatttaCAcTTAA 766_2 -22.62 30675 7-2-1-4 766 TCTATTTAATTTACACTTAA 1-1-1- TcTaTTTaatttaCActTAA 766_3 -20.38 30675 1-3-6- 2-2-3 766 TCTATTTAATTTACACTTAA 3-1-2- TCTaTTtaatttaCaCTtAA 766_4 -20.27 30675 7-1-1- 2-1-2 766 TCTATTTAATTTACACTTAA 2-3-2- TCtatTTaatttaCaCtTAA 766_5 -19.51 30675 6-1-1- 1-1-3 767 ATCTATTTAATTTACACTT 2-1-2- ATcTAtttaattTACAcTT 767_1 -21.49 30677 7-4-1-2 767 ATCTATTTAATTTACACTT 1-1-4- AtCTATttaattTACaCTT 767_2 -23.18 30677 6-3-1-3 767 ATCTATTTAATTTACACTT 4-1-1- ATCTaTttaattTAcACTT 767_3 -22.64 30677 6-2-1-4 767 ATCTATTTAATTTACACTT 5-7-2- ATCTAtttaattTAcaCTT 767_4 -22.78 30677 2-3 767 ATCTATTTAATTTACACTT 1-1-4- AtCTATttaattTaCACTT 767_5 23.52 30677 6-1-1-5 768 ATCTATTTAATTTACACTTA 1-2-4- AtcTATTtaatttACaCtTA 768_1 -21.10 30676 6-2-1- 1-1-2 768 ATCTATTTAATTTACACTTA 1-1-3- AtCTAtTtaatttAcACTTA 768_2 -22.17 30676 1-1-6- 1-1-5 768 ATCTATTTAATTTACACTTA 3-2-2- ATCtaTTtaatttAcACtTA 768_3 -20.60 30676 6-1-1- 2-1-2 768 ATCTATTTAATTTACACTTA 1-1-2- AtCTaTTtaatttaCActTA 768_4 -20.80 30676 1-2-7- 2-2-2 768 ATCTATTTAATTTACACTTA 3-1-1- ATCtAtTtaatttaCacTTA 768_5 -19.72 30676 1-1-7- 1-2-3 769 TATCTATTTAATTTACACTT 1-1-2- TaTCtATttaattTACAcTT 769_1 -22.65 30677 1-2-6- 4-1-2 769 TATCTATTTAATTTACACTT 2-1-1- TAtCtATttaattTAcACTT 769_2 -22.23 30677 1-2-6- 2-1-4 769 TATCTATTTAATTTACACTT 2-1-4- TAtCTATttaattTAcacTT 769_3 -22.66 30677 6-2-3-2 769 TATCTATTTAATTTACACTT 1-3-3- TatcTATttaattTaCACTT 769_4 -22.96 30677 6-1-1-5 769 TATCTATTTAATTTACACTT 1-1-3- TaTCTaTttaattTacaCTT 769_5 -21.15 30677 1-1-6- 1-3-3 770 TATCTATTTAATTTACACT 2-1-3- TAtCTAtttaatTTAcACT 770_1 -22.62 30678 6-3-1-3 770 TATCTATTTAATTTACACT 1-1-4- TaTCTAtttaatTTAcACT 770_2 -22.62 30678 6-3-1-3 770 TATCTATTTAATTTACACT 2-2-2- TAtcTAtttaatTTaCACT 770_3 -21.84 30678 6-2-1-4 770 TATCTATTTAATTTACACT 1-2-3- TatCTAtttaatTtACACT 770_4 -21.72 30678 6-1-1-5 770 TATCTATTTAATTTACACT 4-1-1- TATCtAtttaattTAcACT 770_5 -21.09 30678 7-2-1-3 771 TTATCTATTTAATTTACACT 2-4-1- TTatctAtttaatTTACaCT 771_1 -20.22 30678 6-4-1-2 771 TTATCTATTTAATTTACACT 2-2-3- TTatCTAtttaatTTAcaCT 771_2 -22.76 30678 6-3-2-2 771 TTATCTATTTAATTTACACT 1-1-5- TtATCTAtttaatTTacACT 771_3 -22.87 30678 6-2-2-3 771 TTATCTATTTAATTTACACT 2-2-3- TTatCTAtttaatTtaCACT 771_4 -22.94 30678 6-1-2-4 771 TTATCTATTTAATTTACACT 5-1-1- TTATCtAtttaattTacACT 771_5 -21.68 30678 7-1-2-3 772 TTTATCTATTTAATTTACA 1-1-3- TtTATctatttaATTTaCA 772_1 -19.96 30680 7-4-1-2 772 TTTATCTATTTAATTTACA 4-1-1- TTTAtCtatttaATTtaCA 772_2 -19.70 30680 6-3-2-2 772 TTTATCTATTTAATTTACA 3-1-2- TTTaTCtatttaATtTACA 772_3 -21.24 30680 6-2-1-4 772 TTTATCTATTTAATTTACA 5-7-2- TTTATctatttaATttACA 772_4 -19.82 30680 2-3 772 TTTATCTATTTAATTTACA 1-1-4- TtTATCtatttaAtTTACA 772_5 -21.42 30680 6-1-1-5 773 TTTTATCTATTTAATTTAC 2-1-3- TTtTATctatttAATtTAC 773_1 -19.10 30681 6-3-1-3 773 TTTTATCTATTTAATTTAC 1-1-4- TtTTATctatttAAtTTAC 773_2 -18.66 30681 6-2-1-4 773 TTTTATCTATTTAATTTAC 3-1-2- TTTtATctatttAaTTTAC 773_3 -18.15 30681 6-1-1-5 773 TTTTATCTATTTAATTTAC 1-2-3- TttTATctatttAaTTTAC 773_4 -18.29 30681 6-1-1-5 773 TTTTATCTATTTAATTTAC 2-1-3- TTtTATctatttAatTTAC 773_5 -18.15 30681 6-1-2-4 774 TTTTATCTATTTAATTTACA 1-1-2- TtTTaTctatttaATTTaCA 774_1 -19.84 30680 1-1-7- 4-1-2 774 TTTTATCTATTTAATTTACA 2-1-1- TTtTaTCtatttaATTtACA 774_2 -20.79 30680 1-2-6- 3-1-3 774 TTTTATCTATTTAATTTACA 4-2-1- TTTTatCtatttaATtTACA 774_3 -21.94 30680 6-2-1-4 774 TTTTATCTATTTAATTTACA 1-1-5- TtTTATCtatttaATttaCA 774_4 -21.32 30680 6-2-3-2 774 TTTTATCTATTTAATTTACA 2-2-3- TTttATCtatttaAttTACA 774_5 -20.67 30680 6-1-2-4 775 CTTTTATCTATTTAATTTA 5-7-4- CTTTTatctattTAATtTA 775_1 -21.18 30682 1-2 775 CTTTTATCTATTTAATTTA 5-7-2- CTTTTatctattTAaTTTA 775_2 -21.18 30682 1-4 775 CTTTTATCTATTTAATTTA 5-7-2- CTTTTatctattTAatTTA 775_3 -20.23 30682 2-3 775 CTTTTATCTATTTAATTTA 3-1-1- CTTtTatctattTaATTTA 775_4 -19.83 30682 7-1-1-5 775 CTTTTATCTATTTAATTTA 2-1-2- CTtTTatctattTaAtTTA 775_5 -18.07 30682 7-1-1- 1-1-3 776 CTTTTATCTATTTAATTTAC 1-1-5- CtTTTATctatttAATTtAC 776_1 -21.25 30681 6-4-1-2 776 CTTTTATCTATTTAATTTAC 3-1-1- CTTtTatctatttAATtTAC 776_2 -20.13 30681 8-3-1-3 776 CTTTTATCTATTTAATTTAC 5-8-2- CTTTTatctatttAAtTTAC 776_3 -21.02 30681 1-4 776 CTTTTATCTATTTAATTTAC 1-1-2- CtTTtATctatttAAtTTAC 776_4 -19.49 30681 1-2-6- 2-1-4 776 CTTTTATCTATTTAATTTAC 2-1-4- CTtTTATctatttAAttTAC 776_5 -21.33 30681 6-2-2-3 777 ACTTTTATCTATTTAATTT 4-1-1- ACTTtTatctatTTAAtTT 777_1 -20.04 30683 6-4-1-2 777 ACTTTTATCTATTTAATTT 3-1-2- ACTtTTatctatTTAaTTT 777_2 -20.48 30683 6-3-1-3 777 ACTTTTATCTATTTAATTT 5-7-2- ACTTTtatctatTTaATTT 777_3 -20.54 30683 1-4 777 ACTTTTATCTATTTAATTT 2-2-2- ACttTTatctatTTaATTT 777_4 -19.26 30683 6-2-1-4 777 ACTTTTATCTATTTAATTT 4-1-1- ACTTtTatctatTtaATTT 777_5 -19.21 30683 6-1-2-4 778 ACTTTTATCTATTTAATTTA 2-3-1- ACtttTatctattTAATtTA 778_1 -19.89 30682 7-4-1-2 778 ACTTTTATCTATTTAATTTA 1-1-4- AcTTTTatctattTAaTtTA 778_2 -19.82 30682 7-2-1- 1-1-2 778 ACTTTTATCTATTTAATTTA 3-2-1- ACTttTatctattTAatTTA 778_3 -20.13 30682 7-2-2-3 778 ACTTTTATCTATTTAATTTA 4-9-1- ACTTttatctattTaATTTA 778_4 -21.14 30682 1-5 778 ACTTTTATCTATTTAATTTA 2-1-3- ACtTTTatctattTaATTTA 778_5 -21.49 30682 7-1-1-5 779 ACTTTTATCTATTTAATT 2-1-3- ACtTTTatctatTTaATT 779_1 -18.25 30684 6-2-1-3 779 ACTTTTATCTATTTAATT 4-1-1- ACTTtTatctattTAATT 779_2 -19.17 30684 7-5 779 ACTTTTATCTATTTAATT 3-1-2- ACTtTTatctattTAATT 779_3 -19.17 30684 7-5 779 ACTTTTATCTATTTAATT 2-1-3- ACtTTTatctattTAATT 779_4 -18.79 30684 7-5 779 ACTTTTATCTATTTAATT 1-1-4- AcTTTTatctattTAATT 779_5 -18.42 30684 7-5 780 AACTTTTATCTATTTAATT 5-7-3- AACTTttatctaTTTaATT 780_1 -19.61 30684 1-3 780 AACTTTTATCTATTTAATT 5-8-3- AACTTttatctatTTAaTT 780_2 -18.68 30684 1-2 780 AACTTTTATCTATTTAATT 4-1-1- AACTtTtatctatTTAaTT 780_3 -18.17 30684 7-3-1-2 780 AACTTTTATCTATTTAATT 1-1-4- AaCTTTtatctatTTaATT 780_4 -18.45 30684 7-2-1-3 780 AACTTTTATCTATTTAATT 5-9-5 AACTTttatctattTAATT 780_5 -19.19 30684 781 AACTTTTATCTATTTAAT 5-8-5 AACTTttatctatTTAAT 781_1 -18.18 30685 782 AACTTTTATCTATTTAATTT 1-1-1- AaCtTTTatctatTTAAtTT 782_1 -19.40 30683 1-3-6- 4-1-2 782 AACTTTTATCTATTTAATTT 4-2-1- AACTttTatctatTTAaTTT 782_2 -20.41 30683 6-3-1-3 782 AACTTTTATCTATTTAATTT 5-1-1- AACTTtTatctatTTaATTT 782_3 -21.20 30683 6-2-1-4 782 AACTTTTATCTATTTAATTT 2-1-4- AAcTTTTatctatTtaATTT 782_4 -19.21 30683 6-1-2-4 782 AACTTTTATCTATTTAATTT 1-1-2- AaCTtTTatctattTAaTTT 782_5 -19.40 30683 1-2-7- 2-1-3 783 TAACTTTTATCTATTTAAT 2-1-3- TAaCTTttatctATTTaAT 783_1 -19.91 30685 6-4-1-2 783 TAACTTTTATCTATTTAAT 2-1-3- TAaCTTttatctATtTAAT 783_2 -19.93 30685 6-2-1-4 783 TAACTTTTATCTATTTAAT 5-7-2- TAACTtttatctATtTaAT 783_3 -18.79 30685 1-1-1-2 783 TAACTTTTATCTATTTAAT 1-1-4- TaACTTttatctAtTTAAT 783_4 -19.16 30685 6-1-1-5 783 TAACTTTTATCTATTTAAT 5-9-5 TAACTtttatctatTTAAT 783_5 -19.60 30685 784 TAACTTTTATCTATTTAATT 4-1-1- TAACtTttatctaTtTAaTT 784_1 -18.83 30684 7-1-1- 2-1-2 784 TAACTTTTATCTATTTAATT 2-1-4- TAaCTTTtatctatTTAaTT 784_2 -20.71 30684 7-3-1-2 784 TAACTTTTATCTATTTAATT 2-1-3- TAaCTTttatctatTTaATT 784_3 -19.87 30684 8-2-1-3 784 TAACTTTTATCTATTTAATT 1-1-5- TaACTTTtatctatTTaATT 784_ -20.35 30684 7-2-1-3 784 TAACTTTTATCTATTTAATT 5-10-5 TAACTtttatctattTAATT 784_5 -20.61 30684 785 TAACTTTTATCTATTTAA 5-7-2- TAACTtttatctATtTAA 785_1 -18.07 30686 1-3 786 ATAACTTTTATCTATTTAA 3-1-2- ATAaCTtttatcTATTtAA 786_1 -20.14 30686 6-4-1-2 786 ATAACTTTTATCTATTTAA 4-1-1- ATAAcTtttatcTATtTAA 786_2 -20.03 30686 6-3-1-3 786 ATAACTTTTATCTATTTAA 2-1-3- ATaACTtttatcTAtTTAA 786_3 -20.33 30686 6-2-1-4 786 ATAACTTTTATCTATTTAA 3-1-2- ATAaCTtttatcTAttTAA 786_4 -19.84 30686 6-2-2-3 786 ATAACTTTTATCTATTTAA 5-7-1- ATAACttttatcTaTTTAA 786_5 -20.30 30686 1-5 787 ATAACTTTTATCTATTTAAT 3-1-3- ATAaCTTttatctATTtaAT 787_1 -20.73 30685 6-3-2-2 787 ATAACTTTTATCTATTTAAT 2-1-4- ATaACTTttatctATtTAAT 787_2 -21.66 30685 6-2-1-4 787 ATAACTTTTATCTATTTAAT 3-1-2- ATAaCTtttatctAttTAAT 787_3 -19.93 30685 7-1-2-4 787 ATAACTTTTATCTATTTAAT 4-2-1- ATAActTttatctaTTTaAT 787_4 -18.98 30685 7-3-1-2 787 ATAACTTTTATCTATTTAAT 2-1-4- ATaACTTttatctatTTAAT 787_5 -21.13 30685 8-5 788 TATAACTTTTATCTATTTA 1-1-2- TaTAaCttttatCTATtTA 788_1 -21.10 30687 1-1-6- 4-1-2 788 TATAACTTTTATCTATTTA 2-2-2- TAtaACttttatCTAtTTA 788_2 -20.60 30687 6-3-1-3 788 TATAACTTTTATCTATTTA 3-1-2- TATaACttttatCTaTTTA 788_3 -22.09 30687 6-2-1-4 788 TATAACTTTTATCTATTTA 5-7-1- TATAActtttatCtATTTA 788_4 -21.33 30687 1-5 788 TATAACTTTTATCTATTTA 4-1-1- TATAaCttttatcTAttTA 788_5 -20.13 30687 7-2-2-2 789 TATAACTTTTATCTATTTAA 4-1-1- TATAaCttttatcTATTtAA 789_1 -21.18 30686 7-4-1-2 789 TATAACTTTTATCTATTTAA 2-2-3- TAtaACTtttatcTATtTAA 789_2 -21.32 30686 6-3-1-3 789 TATAACTTTTATCTATTTAA 1-1-5- TaTAACTtttatcTAtTTAA 789_3 -21.97 30686 6-2-1-4 789 TATAACTTTTATCTATTTAA 3-1-2- TATaACttttatcTaTtTAA 789_4 -19.86 30686 7-1-1- 1-1-3 789 TATAACTTTTATCTATTTAA 4-2-1- TATAacTtttatcTatTTAA 789_5 -20.09 30686 6-1-2-4 790 TTATAACTTTTATCTATTT 2-1-3- TTaTAActtttaTCTAtTT 790_1 -21.00 30688 6-4-1-2 790 TTATAACTTTTATCTATTT 5-7-2- TTATAacttttaTCtaTTT 790_2 -20.52 30688 2-3 790 TTATAACTTTTATCTATTT 4-1-1- TTATaActtttaTcTATTT 790_3 -21.08 30688 6-1-1-5 790 TTATAACTTTTATCTATTT 4-1-1- TTATaActtttatCTAtTT 790_4 -20.46 30688 7-3-1-2 790 TTATAACTTTTATCTATTT 2-1-3- TTaTAActtttatcTATTT 790_5 -19.98 30688 8-5 791 TTATAACTTTTATCTATT 5-7-3- TTATAacttttaTCTaTT 791_1 -20.32 30689 1-2 791 TTATAACTTTTATCTATT 5-7-1- TTATAacttttaTcTATT 791_2 -19.99 30689 1-4 791 TTATAACTTTTATCTATT 4-1-1- TTATaActtttatCTATT 791_3 -20.40 30689 7-5 791 TTATAACTTTTATCTATT 4-9-5 TTATaacttttatCTATT 791_4 -19.98 30689 791 TTATAACTTTTATCTATT 2-1-3- TTaTAActtttatCTATT 791_5 -19.81 30689 7-5 792 TTATAACTTTTATCTATTTA 1-2-1- TtaTaACttttatCTAttTA 792_1 -20.10 30687 1-2-6- 3-2-2 792 TTATAACTTTTATCTATTTA 3-2-1- TTAtaActtttatCtATtTA 792_2 -18.80 30687 7-1-1- 2-1-2 792 TTATAACTTTTATCTATTTA 4-1-2- TTATaACttttatCtatTTA 792_3 -21.34 30687 6-1-3-3 792 TTATAACTTTTATCTATTTA 2-1-2- TTaTAaCttttatcTAtTTA 792_4 -20.83 30687 1-1-7- 2-1-3 792 TTATAACTTTTATCTATTTA 1-1-4- TtATAActtttatcTaTTTA 792_5 -19.94 30687 8-1-1-4 793 CTTATAACTTTTATCTATT 1-1-1- CtTaTAacttttATCtaTT 793_1 -19.45 30689 1-2-6- 3-2-2 793 CTTATAACTTTTATCTATT 1-2-3- CttATAacttttAtCTATT 793_2 -21.25 30689 6-1-1-5 793 CTTATAACTTTTATCTATT 3-2-1- CTTatAacttttatCTATT 793_3 -20.78 30689 8-5 793 CTTATAACTTTTATCTATT 1-1-3- CtTATaacttttatCTaTT 793_4 -19.82 30689 9-2-1-2 793 CTTATAACTTTTATCTATT 5-9-1- CTTATaacttttatCtATT 793_5 -20.81 30689 1-3 794 CTTATAACTTTTATCTAT 5-7-3- CTTATaacttttATCtAT 794_1 -21.02 30690 1-2 794 CTTATAACTTTTATCTAT 1-1-3- CtTATaacttttAtCTAT 794_2 -20.04 30690 7-1-1-4 794 CTTATAACTTTTATCTAT 2-2-1- CTtaTaacttttaTCTAT 794_3 -19.59 30690 8-5 794 CTTATAACTTTTATCTAT 3-1-2- CTTaTAacttttatCTAT 794_4 -20.86 30690 8-4 794 CTTATAACTTTTATCTAT 5-10-3 CTTATaacttttatcTAT 794_5 -19.99 30690 795 CTTATAACTTTTATCTATTT 1-1-1- CtTatAActtttaTCtAtTT 795_1 -18.22 30688 2-2-6- 2-1-1- 1-2 795 CTTATAACTTTTATCTATTT 1-1-1- CtTaTAacttttatCTaTTT 795_2 -20.86 30688 1-2-8- 2-1-3 795 CTTATAACTTTTATCTATTT 2-1-2- CTtATaActtttatCTatTT 795_3 -20.54 30688 1-1-7- 2-2-2 795 CTTATAACTTTTATCTATTT 3-2-1- CTTatAacttttatCtAtTT 795_4 -18.19 30688 8-1-1- 1-1-2 795 CTTATAACTTTTATCTATTT 1-2-2- CttATaActtttatctATTT 795_5 -18.61 30688 1-1-9-4 796 CTTATAACTTTTATCTA 5-6-2- CTTATaactttTAtCTA 796_1 -21.44 30691 1-3 796 CTTATAACTTTTATCTA 5-6-1- CTTATaactttTatCTA 796_2 -20.31 30691 2-3 796 CTTATAACTTTTATCTA 1-1-3- CtTATaacttttATCTA 796_3 -19.90 30691 7-5 796 CTTATAACTTTTATCTA 3-1-1- CTTaTaacttttaTCTA 796_4 -18.77 30691 8-4 796 CTTATAACTTTTATCTA 2-1-2- CTtATaacttttaTCTA 796_5 -18.43 30691 8-4 797 GCTTATAACTTTTATCTA 2-2-2- GCttATaactttTAtcTA 797_1 -21.32 30691 6-2-2-2 797 GCTTATAACTTTTATCTA 4-9-1- GCTTataacttttAtCTA 797_2 -21.88 30691 1-3 797 GCTTATAACTTTTATCTA 2-12-4 GCttataacttttaTCTA 797_3 -20.47 30691 797 GCTTATAACTTTTATCTA 2-1-1- GCtTaTaacttttatCTA 797_4 -20.94 30691 1-1-9-3 797 GCTTATAACTTTTATCTA 1-1-4- GcTTATaacttttatcTA 797_5 -19.62 30691 10-2 798 GCTTATAACTTTTATCT 2-9-1- GCttataacttTtaTCT 798_1 -18.54 30692 2-3 798 GCTTATAACTTTTATCT 2-10-5 GCttataactttTATCT 798_2 -20.90 30692 798 GCTTATAACTTTTATCT 4-8-1- GCTTataactttTaTCT 798_3 -21.40 30692 1-3 798 GCTTATAACTTTTATCT 2-1-2- GCtTAtaacttttATCT 798_4 -21.00 30692 8-4 798 GCTTATAACTTTTATCT 5-10-2 GCTTAtaacttttatCT 798_5 -20.68 30692 799 TGCTTATAACTTTTATC 3-8-3- TGCttataactTTTaTC 799_1 -19.59 30693 1-2 799 TGCTTATAACTTTTATC 3-8-2- TGCttataactTTtATC 799_2 -19.26 30693 1-3 799 TGCTTATAACTTTTATC 2-10-5 TGcttataacttTTATC 799_3 -18.08 30693 799 TGCTTATAACTTTTATC 5-8-4 TGCTTataactttTATC 799_4 -22.34 30693 799 TGCTTATAACTTTTATC 3-10-4 TGCttataactttTATC 799_5 -19.90 30693 800 TGCTTATAACTTTTATCT 3-9-3- TGCttataacttTTAtCT 800_1 -22.27 30692 1-2 800 TGCTTATAACTTTTATCT 2-2-2- TGctTAtaactttTATCT 800_2 -22.61 30692 7-5 800 TGCTTATAACTTTTATCT 3-10-1- TGCttataactttTaTCT 800_3 -21.45 30692 1-3 800 TGCTTATAACTTTTATCT 1-1-1- TgCtTAtaacttttATCT 800_4 -20.79 30692 1-2-8-4 800 TGCTTATAACTTTTATCT 4-1-1- TGCTtAtaacttttatCT 800_5 -20.89 30692 10-2 801 CTGCTTATAACTTTTATC 2-1-1- CTgCttataactTTtATC 801_1 -20.05 30693 8-2-1-3 801 CTGCTTATAACTTTTATC 4-8-1- CTGCttataactTttaTC 801_2 -21.02 30693 3-2 801 CTGCTTATAACTTTTATC 2-1-1- CTgCttataactttTATC 801_3 -20.69 30693 10-4 801 CTGCTTATAACTTTTATC 1-1-2- CtGCttataactttTaTC 801_4 -18.86 30693 10-1-1- 2 801 CTGCTTATAACTTTTATC 1-1-4- CtGCTTataacttttATC 801_5 -21.47 30693 9-3 802 CTCTGCTTATAACTTTT 1-1-1- CtCtGcttataACtTTT 802_1 -18.92 30696 1-1-6- 2-1-3 802 CTCTGCTTATAACTTTT 1-1-1- CtCtGcttataaCTtTT 802_2 -18.47 30696 1-1-7- 2-1-2 802 CTCTGCTTATAACTTTT 1-1-2- CtCTgcttataaCtTTT 802_3 -19.44 30696 8-1-1-3 802 CTCTGCTTATAACTTTT 1-2-2- CtcTGcttataaCtTTT 802_4 -19.02 30696 7-1-1-3 802 CTCTGCTTATAACTTTT 3-1-1- CTCtGcttataacttTT 802_5 -18.16 30696 10-2 803 CCTCTGCTTATAACTTT 1-1-2- CcTCtgcttatAAcTTT 803_1 -20.60 30697 7-2-1-3 803 CCTCTGCTTATAACTTT 2-9-1- CCtctgcttatAactTT 803_2 -19.28 30697 3-2 803 CCTCTGCTTATAACTTT 2-2-1- CCtcTgcttataActTT 803_3 -20.58 30697 7-1-2-2 803 CCTCTGCTTATAACTTT 1-2-1- CctCtgcttataActTT 803_4 -18.06 30697 8-1-2-2 803 CCTCTGCTTATAACTTT 2-1-1- CCtCtgcttataaCtTT 803_5 -21.12 30697 9-1-1-2 804 CTACTATACTTTCCTCT 3-8-2- CTActatacttTCctCT 804_1 -22.54 30709 2-2 804 CTACTATACTTTCCTCT 1-1-1- CtActatactttCCtCT 804_2 -21.39 30709 9-2-1-2 804 CTACTATACTTTCCTCT 1-2-1- CtaCtatactttCctCT 804_3 -19.70 30709 8-1-2-2 804 CTACTATACTTTCCTCT 2-11-1- CTactatactttcCtCT 804_4 -20.45 30709 1-2 804 CTACTATACTTTCCTCT 1-3-1- CtacTatactttcCtCT 804_5 -19.77 30709 8-1-1-2 805 TCTACTATACTTTCCTCT 2-1-1- TCtActatactttCctCT 805_1 -21.40 30709 9-1-2-2 805 TCTACTATACTTTCCTCT 2-2-1- TCtaCtatactttCctCT 805_2 -22.20 30709 8-1-2-2 805 TCTACTATACTTTCCTCT 2-11-1- TCtactatactttCctCT 805_3 -21.20 30709 2-2 805 TCTACTATACTTTCCTCT 2-1-1- TCtActatactttcCtCT 805_4 -21.52 30709 10-1-1- 2 805 TCTACTATACTTTCCTCT 2-2-1- TCtaCtatactttcCtCT 805_5 -22.32 30709 9-1-1-2 806 TTCTACTATACTTTCCT 1-1-1- TtCtactatacTttcCT 806_1 -18.06 30711 8-1-3-2 806 TTCTACTATACTTTCCT 1-2-1- TtcTactatacTttcCT 806_2 -18.02 30711 7-1-3-2 806 TTCTACTATACTTTCCT 1-1-1- TtCtActatactTtCCT 806_3 -20.41 30711 1-1-7- 1-1-3 806 TTCTACTATACTTTCCT 1-1-1- TtCtactatacttTCCT 806_4 -20.90 30711 10-4 806 TTCTACTATACTTTCCT 1-1-1- TtCtActatactttCCT 806_5 -20.11 30711 1-1-9-3 807 TTCTACTATACTTTCCTC 1-2-1- TtcTactatactTtCcTC 807_1 -19.51 30710 8-1-1- 1-1-2 807 TTCTACTATACTTTCCTC 1-1-1- TtCtaCtatactTtccTC 807_2 -19.77 30710 2-1-6- 1-3-2 807 TTCTACTATACTTTCCTC 1-1-1- TtCtActatactttCcTC 807_3 -19.44 30710 1-1-9- 1-1-2 807 TTCTACTATACTTTCCTC 1-1-1- TtCtactatactttcCTC 807_4 -20.04 30710 12-3 807 TTCTACTATACTTTCCTC 1-2-1- TtcTaCtatactttccTC 807_5 -19.43 30710 1-1-10- 2 808 TTTCCATCTACTATTAAT 1-1-3- TtTCCatctactATTaAT 808_1 -21.43 39804 7-3-1-2 808 TTTCCATCTACTATTAAT 2-1-2- TTtCCatctactAtTaAT 808_2 -19.50 39804 7-1-1- 1-1-2 808 TTTCCATCTACTATTAAT 1-1-4- TtTCCAtctactAttAAT 808_3 -20.72 39804 6-1-2-3 808 TTTCCATCTACTATTAAT 2-1-2- TTtCCatctactaTtAAT 808_4 -19.43 39804 8-1-1-3 808 TTTCCATCTACTATTAAT 4-1-1- TTTCcAtctactatTAAT 808_5 -20.12 39804 8-4 809 TTTCCATCTACTATTAA 5-6-3- TTTCCatctacTATtAA 809_1 -21.74 39805 1-2 809 TTTCCATCTACTATTAA 2-1-2- TTtCCatctacTAtTAA 809_2 -20.76 39805 6-2-1-3 809 TTTCCATCTACTATTAA 1-1-3- TtTCCatctacTaTTAA 809_3 -20.75 39805 6-1-1-4 809 TTTCCATCTACTATTAA 2-1-2- TTtCCatctactATTAA 809_4 -20.54 39805 7-5 809 TTTCCATCTACTATTAA 5-9-3 TTTCCatctactatTAA 809_5 -20.18 39805 810 GTTTCCATCTACTATTA 3-9-2- GTTtccatctacTAtTA 810_1 -20.81 39806 1-2 810 GTTTCCATCTACTATTA 1-1-1- GtTtCcatctacTaTTA 810_2 -19.35 39806 1-1-7- 1-1-3 810 GTTTCCATCTACTATTA 2-2-1- GTttCcatctacTatTA 810_3 -19.64 39806 7-1-2-2 810 GTTTCCATCTACTATTA 3-1-1- GTTtCcatctactATTA 810_4 -21.37 39806 8-4 810 GTTTCCATCTACTATTA 1-2-2- GttTCcatctactatTA 810_5 -18.14 39806 10-2 811 AATACAAAATCATCTTAC 3-1-2- AATaCAaaatcaTcTTAC 811_1 -18.05 39836 6-1-1-4 811 AATACAAAATCATCTTAC 4-9-5 AATAcaaaatcatCTTAC 811_2 -18.25 39836 811 AATACAAAATCATCTTAC 3-1-2- AATaCAaaatcatCTTAC 811_3 -19.20 39836 7-5 811 AATACAAAATCATCTTAC 2-1-3- AAtACAaaatcatCTTAC 811_4 -18.12 39836 7-5 811 AATACAAAATCATCTTAC 1-1-4- AaTACAaaatcatCTTAC 811_5 -19.50 39836 7-5 812 AATACAAAATCATCTTACA 2-2-2- AAtaCAaaatcaTCTTaCA 812_1 -20.31 39835 6-4-1-2 812 AATACAAAATCATCTTACA 4-8-3- AATAcaaaatcaTCTtaCA 812_2 -19.80 39835 2-2 812 AATACAAAATCATCTTACA 3-1-2- AATaCAaaatcaTCtTACA 812_3 -21.91 39835 6-2-1-4 812 AATACAAAATCATCTTACA 1-1-4- AaTACAaaatcatCTtaCA 812_4 -19.93 39835 7-2-2-2 812 AATACAAAATCATCTTACA 5-8-1- AATACaaaatcatCtTACA 812_5 -20.93 39835 1-4 813 TAATACAAAATCATCTTA 1-1-4- TaATACaaaatcATCtTA 813_1 -18.46 39837 6-3-1-2 813 TAATACAAAATCATCTTA 5-8-5 TAATAcaaaatcaTCTTA 813_2 -19.57 39837 813 TAATACAAAATCATCTTA 5-9-4 TAATAcaaaatcatCTTA 813_3 -18.44 39837 813 TAATACAAAATCATCTTA 2-1-3- TAaTACaaaatcatCTTA 813_4 -18.20 39837 8-4 813 TAATACAAAATCATCTTA 1-1-4- TaATACaaaatcatCTTA 813_5 -18.18 39837 8-4 814 TAATACAAAATCATCTTAC 2-1-3- TAaTACaaaatcATCTtAC 814_1 -19.95 39836 6-4-1-2 814 TAATACAAAATCATCTTAC 4-1-1- TAATaCaaaatcATCtTAC 814_2 -20.22 39836 6-3-1-3 814 TAATACAAAATCATCTTAC 1-2-3- TaaTACaaaatcAtCTTAC 814_3 -19.14 39836 6-1-1-5 814 TAATACAAAATCATCTTAC 5-8-2- TAATAcaaaatcaTCtTAC 814_4 -19.90 39836 1-3 814 TAATACAAAATCATCTTAC 4-1-1- TAATaCaaaatcatCTTAC 814_5 -19.94 39836 8-5 815 TAATACAAAATCATCTTACA 3-2-2- TAAtaCAaaatcaTCtTaCA 815_1 -20.84 39835 6-2-1- 1-1-2 815 TAATACAAAATCATCTTACA 2-3-1- TAataCaaaatcatCTtACA 815_2 -18.77 39835 8-2-1-3 815 TAATACAAAATCATCTTACA 2-1-2- TAaTAcAaaatcatCTtaCA 815_3 -19.66 39835 1-1-7- 2-2-2 815 TAATACAAAATCATCTTACA 1-1-1- TaAtACaaaatcatCtTACA 815_4 -19.11 39835 1-2-8- 1-1-4 815 TAATACAAAATCATCTTACA 4-10-1- TAATacaaaatcatCtTaCA 815_5 -19.22 39835 1-1-1-2 816 TCTGTATACACCATCCCA 2-10-1- TCtgtatacaccAtCcCA 816_1 -24.49 46389 1-1-1-2 816 TCTGTATACACCATCCCA 2-3-1- TCtgtAtacaccAtccCA 816_2 -23.81 46389 6-1-3-2 816 TCTGTATACACCATCCCA 2-10-1- TCtgtatacaccAtccCA 816_3 -23.72 46389 3-2 816 TCTGTATACACCATCCCA 2-1-1- TCtGtatacaccatCcCA 816_4 -24.75 46389 10-1-1- 2 816 TCTGTATACACCATCCCA 2-3-1- TCtgtAtacaccatCcCA 816_5 -24.53 46389 8-1-1-2 816 TCTGTATACACCATCCCA 2-3-1- TCtgtAtacaccatccCA 816_6 -23.76 46389 10-2 817 TTCTGACTCCCTATCCA 1-1-1- TtCtgactccctatcCA 817_1 -22.56 46417 12-2 818 TTTCTGACTCCCTATCC 1-2-1- TttCtgactccctatCC 818_1 -22.64 46418 11-2

Designs refer to the gapmer design, F-G-F′, where each number represents the number of consecutive modified nucleosides, e.g 2′ modified nucleosides (first number=5′ flank), followed by the number of DNA nucleosides (second number=gap region), followed by the number of modified nucleosides, e.g 2′ modified nucleosides (third number=3′ flank), optionally preceded by or followed by further repeated regions of DNA and LNA, which are not necessarily part of the contiguous sequence that is complementary to the target nucleic acid. For some oligonucleotides in table 3 the flanks are mixed flanks, such flanks start and end with a 2′ modified nucleosides, in these cases the gap region is the number above 5 not located at the 5′ or 3′ terminal in of the design.

For the oligonucleotide compounds capital letters represent beta-D-oxy LNA nucleosides, lowercase letters represent DNA nucleosides, all LNA C are 5-methyl cytosine, and 5-methyl DNA cytosines are presented by “e”, all internucleoside linkages are phosphorothioate internucleoside linkages.

Oligonucleotides with an EX-EX indication as Start on SEQ ID NO: 1 are exon-exon spanning oligonucleotides designed to be complementary across exon-exon junctions of SNHG14-023 (ENST00000554726). The oligonucleotides primarily span exon2 and exon3 (i.e. are complementary to a region in exon2 and a region in exon 3)

Oligonucleotide Synthesis

Oligonucleotide synthesis is generally known in the art. Below is a protocol which may be applied. The oligonucleotides of the present invention may have been produced by slightly varying methods in terms of apparatus, support and concentrations used.

Oligonucleotides are synthesized on uridine universal supports using the phosphoramidite approach on a MerMadel2 or an Oligomaker DNA/RNA synthesizer at 1-4 μmol scale. At the end of the synthesis, the oligonucleotides are cleaved from the solid support using aqueous ammonia for 5-16 hours at 60° C. The oligonucleotides are purified by reverse phase HPLC (RP-HPLC) or by solid phase extractions and characterized by UPLC, and the molecular mass is further confirmed by ESI-MS.

Elongation of the Oligonucleotide:

The coupling of β-cyanoethyl-phosphoramidites (DNA-A(Bz), DNA-G(ibu), DNA-C(Bz), DNA-T, LNA-5-methyl-C(Bz), LNA-A(Bz), LNA-G(dmf), LNA-T or amino-C6 linker) is performed by using a solution of 0.1 M of the 5′-O-DMT-protected amidite in acetonitrile and DCI (4,5-dicyanoimidazole) in acetonitrile (0.25 M) as activator. For the final cycle a phosphoramidite with desired modifications can be used, e.g. a C6 linker for attaching a conjugate group or a conjugate group as such. Thiolation for introduction of phosphorthioate linkages is carried out by using xanthane hydride (0.01 M in acetonitrile/pyridine 9:1). Phosphordiester linkages can be introduced using 0.02 M iodine in THE/Pyridine/water 7:2:1. The rest of the reagents are the ones typically used for oligonucleotide synthesis.

Purification by RP-HPLC:

The crude compounds are purified by preparative RP-HPLC on a Phenomenex Jupiter C18 10μ 150×10 mm column. 0.1 M ammonium acetate pH 8 and acetonitrile is used as buffers at a flow rate of 5 mL/min. The collected fractions are lyophilized to give the purified compound typically as a white solid.

Abbreviations

    • DCI: 4,5-Dicyanoimidazole
    • DCM: Dichloromethane
    • DMF: Dimethylformamide
    • DMT: 4,4′-Dimethoxytrityl
    • THF: Tetrahydrofurane
    • Bz: Benzoyl
    • Ibu: Isobutyryl
    • RP-HPLC: Reverse phase high performance liquid chromatography
      Tm Assay

Oligonucleotide and RNA target duplexes are diluted to 3 mM in 500 ml RNase-free water and mixed with 500 ml 2×Tm-buffer (200 mM NaCl, 0.2 mM EDTA, 20 mM Naphosphate, pH 7.0). The solution is heated to 95° C. for 3 min and then allowed to anneal in room temperature for 30 min. The duplex melting temperatures (Tm) is measured on a Lambda 40 UV/VIS Spectrophotometer equipped with a Peltier temperature programmer PTP6 using PE Templab software (Perkin Elmer). The temperature is ramped up from 20° C. to 95° C. and then down to 25° C., recording absorption at 260 nm. First derivative and the local maximums of both the melting and annealing are used to assess the duplex Tm.

Preparation of Mouse Primary Cortical Neuron Cell Cultures

Primary cortical neuron cultures were prepared from mouse embryo brains of 15 days of age according to standard procedure. In brief, culture plates were coated with Poly-L-Lysine (50 μg/ml Poly-L-Lysine, 10 mM Na-tetraborate, pH 8 buffer) for 2-3 hrs at room temperature. The plates were washed with 1×PBS before use. Harvested mouse embryo brains were dissected and homogenized by a razor blade and submerged into 38 ml dissection medium (HBSS, 0.01 M Hepes, Penicillin/Streptomycin). Then, 2 ml trypsin was added and cells were incubated for 30 min at 37° C. and centrifuged down. The cells were dissolved in 20 ml DMEM (+10% FBS) and passed through a syringe for further homogenization. This was followed by centrifugation at 500 rpm for 15 mins. The cells were dissolved in DMEM (+10% FBS) and seeded in 96 well plates (0.1×10{circumflex over ( )}6 cells/well in 100 μl). The neuronal cell cultures were ready for use directly after seeding.

Screening Oligonucleotides in Mouse Primary Cortical Neuron Cell Cultures

Cells were cultured in growth medium (Gibco Neurobasal medium, B27 supplement, Glutamax, Pencillin-streptomycin) in 96-well plates and incubated with oligonucleotides for 3 days at the desired concentrations. Total RNA was isolated from the cells and the knock-down efficacy was measured by qPCR analysis using the qScript™ XLT One-Step RT-qPCR ToughMix®, Low ROX™ kit from Quanta Bioscience (95134-500). A commercial taqman assays from Thermo Fisher Scientific was used to measure Ube3a_ATS including GAPDH for normalization.

Generation of Human Primary Neuronal Cell Cultures

Any cell lines at any described time point was incubated at 37° C., 5% CO2 concentration and 95% relative humidity.

Human Induced Pluripotent Stem Cells (hiPSC) Culture

Whole human blood samples were obtained from patients diagnosed with Angelman syndrome. The subsequent cultures of primary Peripheral Blood Mononuclear Cells (PMCSs) were enriched for erythroblasts. Patient-specific iPSC lines were generated by reprogramming erythroblast with CytoTune-iPS Sendai Reprogramming Kit (Thermo Fisher Scientific). Derived iPSC lines were maintained in feeder-free conditions using hESC-qualified Matrigel (Corning) in mTESR1 (STEMCELL Technologies) with daily medium replacement. Upon reaching confluence, colonies were dissociated into cell cluster of 50-200 μm in size using Gentle Cell Dissociation Reagent (STEMCELL Technologies) and subcultured at a ratio of 1:10-1:20 in the presence of 10 μM Y-27632 (Calbiochem).

Differentiation into Neural Progenitor Cells (NPC)

Upon induction of neural differentiation iPSC-derived cells were maintained in basal medium composed of equal volumes of DMEM:F12 Glutamax medium and Neurobasal medium (Gibco, Invitrogen), supplemented with 1×B27 (Gibco, Invitrogen), 1×N2 (Gibco, Invitrogen), 0.1 mM beta-mercaptoethanol (Gibco, Invitrogen) and indicated supplements.

Neural progenitor cells (NPCs) were derived from hiPSCs by dual SMAD inhibition and according to published procedures with slight modifications (Chambers et al. 2009 Nat Biotechnol. Vol. 3 pp. 275-80, Boissart et al., 2013 Transl Psychiatry. 3:e294). HiPSCs were dissociated with Accutase (Innovative Cell Technologies Inc.) into a single cell suspension and resuspended in basic medium further supplemented with 10 μM Y-27632 (Calbiochem), 5 ng/ml FGF (Peprotech), 10 μM SB-431542 (Calbiochem) and 100 nM LDN (Calbiochem). Single cell suspension was transferred to AggreWell800 plates (STEMCELL Technologies) enabling the formation of aggregates consisting of 8000 cells. After 5 days neural aggregates were transferred onto plates coated with poly-L-ornithine (Sigma) and laminin (Roche) and allowed to form neural rosettes under continued dual SMAD inhibition (SB-431542 and LDN) in basic medium supplemented with FGF. Neural rosettes were selectively isolated using STEMdiff™ Neural Rosette Selection Reagent (STEMCELL Technologies), replated onto dishes coated with poly-L-ornithine and Laminin521 (BioLamina) and expanded in basic medium supplemented with 10 ng/ml FGF (Peprotech), 10 ng/ml EGF (RnD), and 20 ng/ml BDNF (Peprotech). When reaching confluency, cells were enzymatically dissociated with 0.05% Trypsin/EDTA (Gibco, Invitrogen) and sub-cultured. Continued passaging in basic medium supplemented with FGF, EGF and BDNF leads to a stable neural progenitor cell line (NPC line) within 10 to 20 passages. A stable neural progenitor cell line is defined by its capacity to self-renew and by the expression of the developmental stage-specific markers Sox2 and Nestin. Upon specific stimuli, NPCs differentiate into neuronal (MAP2+, Tau+, HuC/D+) and astroglial (GFAP+) progenies (Dunkley et al., 2015 Proteomics Clin Appl. Vol. 7-8 pp. 684-94).

NPC Culture

Conditions for NPC culture have been described previously and were used with slight modifications (Boissart et al., 2013 Transl Psychiatry. 3:e294). In brief, cells were maintained in dishes coated with Laminin521 (BioLamina) and cultured in basic medium [composed of equal volumes of DMEM:F12 Glutamax medium and Neurobasal medium (Gibco, Invitrogen), supplemented with 1×B27 (Gibco, Invitrogen), 1×N2 (Gibco, Invitrogen), 0.1 mM beta-mercaptoethanol (Gibco, Invitrogen)] and supplemented with 10 ng/ml FGF (Peprotech), 10 ng/ml EGF (RnD), and 20 ng/ml BDNF (Peprotech).

Differentiation into Neuronal Cell Culture

To induce neuronal differentiation of NPC, cells were dissociated with 0.05% Trypsin/EDTA (Gibco, Invitrogen) into single cell suspension and seeded onto Laminin521 (BioLamina) coated dishes at a density of 12.000 cells/cm2 and maintained in basic medium supplemented with 200 ng/ml Shh (Peprotech), 100 ng/ml FGF8 (Peprotech), and 100 μM ascorbic acid phosphate (Sigma) for a period of 7 days. Subsequently, cells were replated in basal medium supplemented with 20 ng/ml BDNF (Peprotech), 10 ng/ml GDNF (Peprotech), 0.5 mM cAMP (BIOLOG Life Science), and 100 μM ascorbic acid phosphate (Sigma) at a density of 45000 cells/cm2 and differentiated for a period of 21 days. At day 21 of differentiation, differentiated neuronal cultures were replated onto the screening-compatible plate format. Replating was performed by dissociating the cultures with Accutase (Innovative Cell Technologies Inc.) into a single cell suspension. Cells were seeded at a density of 200.000 cells/cm2 in presence of 10 μM Y-27632 (a cell-permeable, reversible, inhibitor of Rho kinases from Calbiochem) into the 384 well microtiter plates for final oligonucleotides screening assay. Neuronal cultures were further differentiated for additional 7 days in basal medium supplemented with 20 ng/ml BDNF (Peprotech), 10 ng/ml GDNF (Peprotech), 0.5 mM cAMP (BIOLOG Life Science), and 100 μM ascorbic acid phosphate (Sigma). Differentiation medium was exchanged twice per week. After a total differentiation period of 35 days neuronal cell cultures were ready for oligonucleotide treatment.

Screening Oligonucleotides in Human Neuronal Cell Cultures—384 Well System

For screening, oligonucleotide stocks were pre-diluted to the indicated concentrations with water into 384 well microtiter plates (compound plate). The plate layout served as a treatment template. Two microliter oligonucleotide dilution from each well was transferred from the compound plate to a respective culture plate. All liquid handling was done under sterile conditions in a laminar flow using a semi-automated laboratory robotic system (Beckmancoulter). Neuronal cell cultures were incubated with oligonucleotides for 5 days without media change. Subsequently, neuronal cultures were lysed and processed for qPCR assay with RealTime ready Cell lysis and RNA Virus Master kit (Roche). Liquid handling was performed using a semi-automated laboratory robotic system (Beckmancoulter). Samples were analyzed by a Lightcycler480 real-time PCR system (Roche).

Activity of the oligonucleotides was assessed by qPCR monitoring transcript abundance of UBE3A using the following primers and probes

UBE3a-Sense: Forward primer: (SEQ ID NO: 837) ATATGTGGAAGCCGGAATCT, Reverse primer: (SEQ ID NO: 838) TCCCAGAACTCCCTAATCAGAA, Internal probe labeled with dye FAM: (SEQ ID NO: 839) ATGACGGTGGCTATACCAGG

The RT-qPCR was multiplexed with PPIA (peptidylprolyl isomerase A) as housekeeping gene for normalization. PPIA primers and probe labeled with the dye VIC were purchased from Thermo Fisher Scientific (assay ID Hs99999904_m1). Each plate includes a non-targeting oligonucleotide (mock) as negative control (TTGaataagtggaTGT (SEQ ID NO: 846)) and a reference oligonucleotide CMP ID NO: 411, resulting in up-regulation of UBE3A mRNA.

Selectivity of oligonucleotides was verified by counter screening for SNORD 115 transcript, which is located upstream of SNORD109B on chromosome 15. Expression of SNORD115 was monitored by qPCR using the following primers and probe

Forward primer: (SEQ ID NO: 840) GGGTCAATGATGAGAACCTTAT, Reverse primer (SEQ ID NO: 841) GGGCCTCAGCGTAATCCTATT, Internal probe labeled with the dye FAM: (SEQ ID NO: 842) TTCTGAAGAGAGGTGATGACTTAAAA

The RT-qPCR was multiplexed with PPIA (Thermo Fisher Scientific) upon oligonucleotide treatment.

The reduction of the SNHG14 transcript downstream of SNORD109B (also termed the UBE3A suppressor) was measured by RT-qPCR using the following primers and probe

Forward primer: (SEQ ID NO: 843) ATCCGAGGCATGAATCTCAC, Reverse primer: (SEQ ID NO: 844) CAGGCCAAAACCCTTGATAA, Internal probe labeled with dye FAM: (SEQ ID NO: 845) TTGCTGAGCATTTTTGCATC

The RT-qPCR was multiplexed with PPIA (Thermo Fisher Scientific).

Data are presented as average % expression relative to mock across all plates and normalized to the reference oligonucleotide to account for plate to plate variation.

Screening Oligonucleotides in Human Neuronal Cell Cultures—96 Well System

For screening, oligonucleotide stocks were pre-diluted to the indicated concentrations with water into 96 well microtiter plates (compound plate). The plate layout served as a treatment template. Two microliter oligonucleotide dilution from each well was transferred from the compound plate to a respective culture plate. All liquid handling was done under sterile conditions in a laminar flow using a semi-automated laboratory robotic system (Beckman Coulter). Neuronal cell cultures were incubated with oligonucleotides for 5 days without media change. Subsequently, neuronal cultures were lysed and RNA purified using RNA purification kit Pure Link Pro96 (12173011 A) LifeTechnologies. Liquid handling was performed using a semi-automated laboratory robotic system (Beckmancoulter). qPCR analysis of Ube3a and Ube3a-ATS was carried out on a ViiA™ 7 Real-Time PCR System Thermo Fisher Scientific using the qScript™ XLT 1-Step RT-qPCR ToughMix Low ROX, from Quanta (95134-50).

The following primers and probes were used:

qPCR UBE3a-Sense: Forward primer: (SEQ ID NO: 697) ATATGTGGAAGCCGGAATCT, Reverse primer: (SEQ ID NO: 698) TCCCAGAACTCCCTAATCAGAA, Internal probe labeled with dye FAM: (SEQ ID NO: 699) ATGACGGTGGCTATACCAGG

qPCR SNHG14 transcript downstream of SNORD109B (also termed the UBE3A suppressor): Commercially available primer and probe set from ThermoFisher: Hs01372957_m1. These primers amplifies a 87 bp exon-exon spanning sequence in the Genbank transcript AF400500.1
QPCR GAPDH Transcript:

Commercially available primer and probe set from Thermofisher: Gene Symbol: with following assay details: RefSeq: NM_002046.3, Probe Exon Location:3, Amplicon Size: 122 bp. Corresponding TaqMan Assay ID: Hs99999905_m1.

The RT-qPCR for both Ube3a and Ube3a-ATS was multiplexed with GAPDH as housekeeping gene for normalization. Each plate includes a non-targeting oligonucleotide (mock) as negative control (TTGaataagtggaTGT (SEQ ID NO: 846)) and a reference oligonucleotide CMP ID NO: 211, resulting in up-regulation of UBE3A mRNA. Moreover panel of oligos not targeting Ub3a or SNHG14 transcript downstream of SNORD109B (also termed the UBE3A suppressor) were included to monitor the assay noise and risk of detecting false positives. These were randomly distributed over the plates.

Control Oligonucleotides:

(SEQ ID NO: 819) CGAaccactgaaCAA (SEQ ID NO: 820) CGAaccactgaacAAA (SEQ ID NO: 821) CGAagtgcacaCG (SEQ ID NO: 822) GCGtaaagagaGGT (SEQ ID NO: 823) GAGAaggcacagaCGG (SEQ ID NO: 824) GCGaagtgcacaCGG (SEQ ID NO: 825) GAGaaggcacagaCGG (SEQ ID NO: 826) CGAaccactgAACA (SEQ ID NO: 827) GAAccactgaacAAA (SEQ ID NO: 828) caGCGtaaagagaGG (SEQ ID NO: 829) GCgtaaagagAGG (SEQ ID NO: 830) CGAaccactgaAC (SEQ ID NO: 831) CGAAccactgaaCAAA (SEQ ID NO: 832) AGCgaagtgcacaCGG (SEQ ID NO: 833) AGGtgaagcgaAGTG (SEQ ID NO: 834) TAGTaaactgagCCA (SEQ ID NO: 835) AGAaggcacagaCGG (SEQ ID NO: 836) CCGcagtatggaTCG

Example 1—Oligonucleotide Activity in Mouse Primary Neuronal Cell Cultures

Oligonucleotides targeting the part of SNHG14 long non-coding RNA which is antisense to the UBE3A pre-mRNA (position 55319 to 141053 of SEQ ID NO: 1) were tested for their ability to reduce the SNHG14 long non-coding RNA transcript preventing UBE3A expression (also termed UBE3A suppressor or UBE3A-SUP in the data table) and their ability to induce UBE3A mRNA re-expression in mouse primary cortical neuron cell cultures, obtained as described in the “Materials and methods” section above. The oligonucleotide concentration was 5 microM.

The oligonucleotides were screened according to the protocol for screening in mouse cortical neuron cell cultures described in the section “Materials and methods”. The results are shown in table 4.

TABLE 4 Oligonucleotide activity in primary mouse neuronal cell cultures. CMP % of Mock % of Mock ID NO oligonucleotide UBE3A_SUP sd UBE3A sd 95_1 CTCAtacttgctttaAT 3.6 0.1 154.1 15.1 95_2 CTcatacttgctttaAT 15.9 2.6 119.8 12.4 96_1 ACatctcatacttGCTT 4.0 0.5 149.9 11.5 96_2 ACatctcatacttgcTT 9.3 3.9 139.9 36.4 96_3 ACatctcatacttgCTT 3.1 0.2 143.2 3.9 97_1 ACatctcatactTGCT 4.0 1.5 154.5 10.0 97_2 ACatctcatacttgCT 6.1 1.7 141.1 14.1 97_3 ACatctcatacttGCT 3.7 0.6 162.7 15.0 97_4 ACATctcatacttgCT 5.2 0.4 156.7 24.4 98_1 TAcatctcatactTGCT 5.0 0.9 159.0 15.6 98_2 TAcatctcatacttgCT 15.5 5.3 130.4 3.4 98_3 TACAtctcatacttgCT 4.7 0.4 140.3 38.2 101_1 TACatctcatactTGC 2.6 0.5 152.6 10.2 101_2 TAcatctcatacttGC 19.2 6.0 112.0 15.0 101_3 TAcatctcatactTGC 3.5 0.4 117.2 13.7 101_4 TACAtctcatacttGC 3.0 0.7 140.5 12.4 100_1 CTAcatctcatactTGC 5.4 0.8 160.4 4.1 100_2 CTacatctcatacttGC 9.6 3.7 159.2 14.5 100_3 CTacatctcatactTGC 3.0 0.1 133.2 5.9 99_2 CCtacatctcatacttGC 7.8 1.4 150.7 11.0 99_3 CCtacatctcatactTGC 3.2 0.6 134.7 12.5 99_4 CCtacatctcatacTTGC 2.7 0.2 145.2 4.7 102_1 CCTAcatctcatactTG 5.8 1.7 127.0 24.5 102_2 CCtacatctcatactTG 20.2 6.6 129.7 9.2 102_4 CCTacatctcatacTTG 4.0 0.6 140.2 7.2 102_3 CCTacatctcatactTG 3.9 1.0 133.3 10.0 104_1 CCTacatctcataCTT 6.6 1.5 136.5 8.7 104_3 CCtacatctcatACTT 3.5 0.4 131.4 6.0 103_1 ACCtacatctcataCTT 5.8 1.4 130.8 0.7 103_2 ACctacatctcatacTT 11.4 2.2 123.6 12.4 103_3 ACctacatctcatACTT 5.8 0.8 132.2 4.5 105_1 TACCtacatctcatacTT 5.2 0.8 152.3 7.2 106_1 TTAcctacatctcataCTT 13.3 3.0 140.1 17.5 106_2 TTacctacatctcatacTT 21.0 1.4 116.9 15.0 107_1 ACCTacatctcataCT 6.2 0.9 119.2 3.4 107_2 ACctacatctcataCT 14.3 7.4 142.9 13.7 108_1 TACCtacatctcataCT 5.6 1.0 127.0 10.7 108_2 TAcctacatctcataCT 21.4 12.5 117.1 8.5 109_1 TTacctacatctcaTACT 4.4 0.4 138.9 1.2 109_2 TTacctacatctcataCT 22.9 3.3 117.1 13.0 110_1 TTAcctacatctcaTAC 8.7 2.1 133.2 5.1 110_2 TTacctacatctcatAC 21.0 5.1 111.4 11.1 111_1 GTtacctacatctCATA 8.0 2.4 143.8 14.8 111_2 GTtacctacatctcaTA 19.0 2.3 115.4 4.1 112_1 GTTacctacatctCAT 6.6 1.4 145.5 16.8 112_2 GTtacctacatctcAT 15.8 4.5 120.3 8.1 126_1 TCACtttccagatatCA 8.0 1.9 133.8 5.4 126_3 TCactttccagatatCA 53.4 75.9 112.0 11.4 128_1 ACATgtccctttataTT 16.3 2.5 114.7 11.1 128_2 ACatgtccctttataTT 14.8 1.1 136.9 6.2 129_1 ACAtgtccctttaTAT 11.8 1.9 135.0 14.3 132_1 CTCAtccctccaagaAA 9.1 1.6 131.7 8.4 132_2 CTcatccctccaagaAA 11.2 3.9 159.3 17.7

Example 2—Oligonucleotide activity in human neuronal cell cultures

Oligonucleotides targeting human SNHG14 in the region downstream of SNORD109B corresponding to position 25278410 to 25419462 on chromosome 15 (SEQ ID NO: 1) were tested in patient derived human neuronal cell cultures (see protocol in “Materials and methods” section). The oligonucleotides ability to reduce the SNHG14 transcript in the region downstream of SNORD109B (also termed UBE3A suppressor or UBE3A-SUP in the data table), without affecting expression of SNORD115 was analyzed. Furthermore, the ability to induce UBE3A mRNA re-expression was analyzed.

The oligonucleotides were screened according to the protocol for screening oligonucleotides in human neuronal cell cultures described in the section “Materials and methods” above.

The results are shown in table 5. The expression of UBE3A mRNA has been measured for all compounds, whereas the knock-down of the UBE3A suppressor and the maintenance of SNORD61115 levels have not been analyzed for all compounds.

TABLE 5 Oligonucleotide activity in patient derived human neuronal cell cultures. Start CMP % of Mock % of Mock % of Mock SEQ ID ID Oligo conc Oligo conc Oligo conc NO 1 NO Target 0.2 μM sd 1.0 μM sd 5.0 μM sd  1678  10_1 UBE3A 107 14 88 10 151 8  1679  12_2 UBE3A 100 9 87 14 158 16  1687  20_1 UBE3A 87 7 102 22 213 44  1712  21_1 UBE3A 127 23 166 6 178 13  1712  21_1 UBE3A-SUP 81 3 82 8 72 12  1712  21_1 SNORD115 115 6 142 24 169 26  4167  22_1 UBE3A 87 5 90 8 146 20  4170  27_1 UBE3A 94 16 106 11 170 10  4171  29_2 UBE3A 86 13 100 12 194 35  4172  30_1 UBE3A 96 6 121 12 209 27  9210  35_1 UBE3A 88 5 112 23 195 27 10838  37_1 UBE3A 77 7 85 9 169 24 15565  38_2 UBE3A 93 11 108 6 167 34 22209  42_1 UBE3A 125 16 143 14 180 17 22209  42_1 UBE3A-SUP 108 14 98 15 85 18 22209  42_1 SNORD115 101 14 93 25 127 21 30449  43_1 UBE3A 99 5 95 13 115 8 30451  44_1 UBE3A 99 15 80 20 141 17 30451  44_2 UBE3A 98 31 104 16 119 7 30697  46_1 UBE3A 91 8 87 5 167 20 36066  49_1 UBE3A 95 6 111 10 155 29 36066  49_1 UBE3A-SUP 76 7 84 24 110 31 36066  49_1 SNORD115 99 14 111 20 94 6 36068  50_1 UBE3A 109 15 105 11 92 14 36068  50_1 UBE3A-SUP 122 24 93 28 73 7 36068  50_1 SNORD115 120 15 113 12 99 6 37206  51_1 UBE3A 114 16 101 7 101 3 37206  51_1 UBE3A-SUP 128 21 67 9 84 13 37206  51_1 SNORD115 140 26 110 9 100 11 46130  52_1 UBE3A 139 3 160 1 236 36 46130  52_1 UBE3A-SUP 135 16 133 26 160 32 46130  52_1 SNORD115 104 8 119 14 100 8 48145  59_1 UBE3A 179 3 122 17 115 NA 48170  76_1 UBE3A 85 16 100 8 155 12 48171  80_1 UBE3A 120 7 114 10 172 20 48171  78_1 UBE3A 136 31 103 20 169 11 48172  82_2 UBE3A 96 11 121 4 186 32 48172  84_1 UBE3A 95 14 100 8 158 14 49343  85_1 UBE3A 97 22 121 10 189 17 49722  87_1 UBE3A 111 9 126 11 177 22 52417  92_1 UBE3A 133 7 140 30 140 8 52417  92_1 UBE3A-SUP 88 14 80 14 82 8 52417  92_1 SNORD115 102 8 114 20 91 9 52420  93_1 UBE3A 111 14 120 9 126 16 52420  93_1 UBE3A-SUP 104 23 82 20 79 8 52420  93_1 SNORD115 110 11 114 17 95 7 53953  94_1 UBE3A 117 12 147 15 166 15 53953  94_1 UBE3A-SUP 92 18 81 5 86 22 53953  94_1 SNORD115 124 33 122 17 106 14 60819  95_1 UBE3A 103 11 131 14 175 7 60819  95_1 UBE3A-SUP 93 13 87 3 74 6 60819  95_1 SNORD115 162 19 158 20 201 11 60819  95_2 UBE3A 147 10 129 20 117 2 60819  95_2 UBE3A-SUP 118 24 87 13 83 8 60819  95_2 SNORD115 104 17 118 10 129 6 60823  96_1 UBE3A 115 16 135 19 174 17 60823  96_1 UBE3A-SUP 104 25 93 32 91 11 60823  96_2 UBE3A 108 7 114 9 115 13 60823  96_2 UBE3A-SUP 99 17 92 19 93 10 60824  97_1 UBE3A 111 12 134 23 169 14 60824  97_1 UBE3A-SUP 110 27 105 33 92 10 60824  97_2 UBE3A 124 13 126 12 124 11 60824  97_2 UBE3A-SUP 113 17 107 33 96 20 60824  98_1 UBE3A 111 16 119 11 138 14 60824  98_1 UBE3A-SUP 118 34 98 23 82 19 60824  98_1 SNORD115 109 11 123 18 114 16 60824  98_2 UBE3A 128 10 109 7 136 12 60824  98_2 UBE3A-SUP 91 15 77 11 110 16 60824  98_2 SNORD115 101 3 110 7 124 11 60825  99_1 UBE3A 125 6 115 5 131 10 60825  99_1 UBE3A-SUP 139 18 121 34 127 45 60825  99_1 SNORD115 110 18 112 12 99 19 60825  99_2 UBE3A 120 21 111 11 135 22 60825  99_2 UBE3A-SUP 96 2 79 15 75 11 60825  99_2 SNORD115 104 34 113 22 131 24 60825 100_1 UBE3A 123 34 139 34 145 21 60825 100_1 UBE3A-SUP 104 37 127 46 99 17 60825 100_2 UBE3A 124 46 138 37 145 31 60825 100_2 UBE3A-SUP 111 36 120 47 92 11 60825 101_1 UBE3A 112 18 123 15 150 13 60825 101_1 UBE3A-SUP 96 18 102 14 88 12 60825 101_2 UBE3A 118 15 138 24 139 32 60825 101_2 UBE3A-SUP 100 29 110 39 92 10 60826 102_1 UBE3A 132 17 120 7 125 9 60826 102_1 UBE3A-SUP 113 16 83 5 88 18 60826 102_1 SNORD115 121 36 131 23 100 9 60826 102_2 UBE3A 90 6 116 23 103 7 60826 102_2 UBE3A-SUP 91 7 90 12 64 18 60826 102_2 SNORD115 116 15 146 27 183 28 60827 103_1 UBE3A 106 8 112 10 115 9 60827 103_1 UBE3A-SUP 99 15 110 28 94 8 60827 103_2 UBE3A 107 14 120 13 112 14 60827 103_2 UBE3A-SUP 97 14 118 38 93 20 60827 104_1 UBE3A 128 14 111 9 111 6 60827 104_1 UBE3A-SUP 111 12 97 9 87 19 60827 104_1 SNORD115 114 10 110 12 109 13 60827 104_2 UBE3A 108 10 111 16 109 10 60827 104_2 UBE3A-SUP 103 13 103 33 89 9 60827 105_1 UBE3A 122 13 121 12 121 4 60827 105_1 UBE3A-SUP 119 7 97 15 93 7 60827 105_1 SNORD115 114 21 128 12 118 9 60827 105_2 UBE3A 123 5 110 9 114 8 60827 105_2 UBE3A-SUP 110 11 89 17 94 21 60827 105_2 SNORD115 102 15 108 16 107 18 60827 106_1 UBE3A 114 17 133 23 125 9 60827 106_1 UBE3A-SUP 112 35 103 15 87 12 60827 106_2 UBE3A 110 12 130 22 123 14 60827 106_2 UBE3A-SUP 105 19 107 27 93 10 60828 107_1 UBE3A 83 11 117 13 112 6 60828 107_1 UBE3A-SUP 86 11 114 16 67 7 60828 107_1 SNORD115 108 17 130 21 137 24 60828 107_2 UBE3A 143 42 117 10 122 11 60828 107_2 UBE3A-SUP 116 12 92 4 100 8 60828 107_2 SNORD115 108 4 127 16 108 14 60828 108_1 UBE3A 120 7 127 31 132 31 60828 108_1 UBE3A-SUP 153 33 118 34 89 17 60828 108_1 SNORD115 114 9 114 9 105 15 60828 108_2 UBE3A 122 18 133 26 128 9 60828 108_2 UBE3A-SUP 101 19 100 28 89 17 60828 109_1 UBE3A 108 10 129 14 128 5 60828 109_1 UBE3A-SUP 106 21 107 24 84 8 60828 109_2 UBE3A 109 11 110 8 111 13 60828 109_2 UBE3A-SUP 95 15 86 14 83 9 60829 110_1 UBE3A 104 6 83 3 101 15 60829 110_1 UBE3A-SUP 100 13 95 12 79 4 60829 110_1 SNORD115 126 21 125 6 182 13 60829 110_2 UBE3A 92 7 87 8 96 7 60829 110_2 UBE3A-SUP 99 7 108 9 81 5 60829 110_2 SNORD115 118 15 139 22 198 39 60830 111_1 UBE3A 110 6 122 13 124 10 60830 111_1 UBE3A-SUP 104 14 90 28 79 11 60830 111_2 UBE3A 115 10 120 15 121 10 60830 111_2 UBE3A-SUP 114 20 89 19 87 9 60831 112_1 UBE3A 93 8 94 13 106 10 60831 112_1 UBE3A-SUP 97 1 68 29 82 7 60831 112_1 SNORD115 116 20 110 13 158 20 60831 112_2 UBE3A 83 8 78 7 83 6 60831 112_2 UBE3A-SUP 106 35 80 23 69 9 60831 112_2 SNORD115 107 6 106 8 159 21 62198 113_1 UBE3A 110 3 122 6 134 9 62198 113_1 UBE3A-SUP 113 20 85 19 79 24 62198 113_1 SNORD115 116 18 123 9 91 9 62284 115_1 UBE3A 105 14 98 19 141 36 62422 116_1 UBE3A 130 19 142 29 172 18 62423 117_1 UBE3A 76 8 93 13 171 17 62439 118_1 UBE3A 75 7 88 9 150 19 66378 119_1 UBE3A 96 14 93 5 110 10 77565 126_1 UBE3A 94 6 113 5 125 14 77565 126_1 UBE3A-SUP 83 17 95 33 85 5 77565 126_1 SNORD115 105 11 123 19 152 15 77565 126_2 UBE3A 95 5 126 9 111 2 77565 126_2 UBE3A-SUP 77 27 106 21 83 15 77565 126_2 SNORD115 115 17 157 13 180 15 92321 128_1 UBE3A 102 7 91 5 111 13 92321 128_1 UBE3A-SUP 115 3 104 25 91 13 92321 128_1 SNORD115 135 9 132 12 196 35 92321 128_2 UBE3A 91 5 96 8 104 8 92321 128_2 UBE3A-SUP 112 20 92 20 79 7 92321 128_2 SNORD115 125 7 111 13 169 12 92322 129_1 UBE3A 101 5 103 2 110 7 92322 129_1 UBE3A-SUP 99 39 113 12 94 13 92322 129_1 SNORD115 124 25 114 6 140 13 92322 129_2 UBE3A 93 2 100 4 113 16 92322 129_2 UBE3A-SUP 109 4 102 22 85 7 92322 129_2 SNORD115 103 11 99 9 152 31 97154 132_1 UBE3A 100 10 128 13 142 13 97154 132_1 UBE3A-SUP 103 9 115 8 109 6 97154 132_1 SNORD115 49 7 90 12 143 25 97154 132_2 UBE3A 111 8 128 17 128 17 97154 132_2 UBE3A-SUP 95 7 116 9 105 13 97154 133_2 SNORD115 86 7 106 9 121 9 97154 133_1 UBE3A 101 3 107 11 124 19 97154 133_1 UBE3A-SUP 112 9 117 7 146 25 97154 133_1 SNORD115 60 7 110 15 141 15 97154 133_2 UBE3A 94 13 116 14 138 12 97154 133_2 UBE3A-SUP 116 6 128 13 148 38 97154 132_2 SNORD115 70 5 108 9 160 34 106137 137_1 UBE3A 83 12 74 11 124 20 109404 138_1 UBE3A 80 20 92 7 120 21 110766 139_1 UBE3A 76 5 85 12 121 17 114826 140_1 UBE3A 87 10 88 11 136 9 118637 143_1 UBE3A 83 7 104 30 141 28 118639 144_1 UBE3A 74 17 31 39 106 33 124160 145_2 UBE3A 89 6 95 10 115 25 125499 146_1 UBE3A 83 13 76 7 124 16 125499 146_2 UBE3A 123 30 79 14 102 13 125538 150_2 UBE3A 82 17 82 7 119 24

Of the 187 compounds tested approximately 90% showed re-expression of UBE3A when compared to the mock oligonucleotide at the 5 micro Molar concentration. The number of oligonucleotides capable of inducing re-expression of UBE3A is higher in the region between position 1 to 55318 of SEQ ID NO: 1 (non-overlapping region) then in the region complementary to UBE3A coding region (overlapping region. FIG. 2 plots the distribution of the oligonucleotides according to their position on chromosome 15 versus the UBE3A mRNA expression relative to the mock oligonucleotide.

For the oligonucleotides where SNORD115 has been tested there is no significant down regulation when compared to mock at 1 and 5 microM.

Example 3—Activity of Oligonucleotides Targeting the SNHG14 Transcript in the Region Downstream of SNORD109B and Upstream of the Region Antisense to to the UBE3A Pre-mRNA

Oligonucleotides targeting position 4806-54939 of SEQ ID NO: 1 were tested in patient derived human neuronal cell cultures (see protocol in “Materials and methods” section). The oligonucleotides ability to reduce the SNHG14 transcript in the region downstream of SNORD109B (also termed UBE3A suppressor or UBE3A-SUP in the data table. Furthermore, the ability to induce UBE3A mRNA re-expression was analyzed.

The oligonucleotides were screened according to the protocol for screening oligonucleotides in human neuronal cell cultures described in the section “Materials and methods”—“Screening oligonucleotides in human neuronal cell cultures—96 well system”

The results are shown in table 6.

TABLE 6 Oligonucleotide activity in patient derived human neuronal cell cultures. Start SEQ CMP ID Conc % of Mock % of Mock ID NO 1 NO μM UBE3A-SUP sd UBE3A sd  4806 151_1 0.2 66 2 125 NA  4806 151_1 1 53 10 NA NA  4808 152_1 0.2 49 6 167 NA  4808 152_1 1 33 4 289 NA  4809 153_1 0.2 41 1 208 NA  4809 153_1 1 29 10 NA NA  4811 154_1 0.2 48 3 282 NA  4811 154_1 1 37 5 331 NA  4812 155_1 0.2 35 5 286 64  4812 155_1 1 32 3 327 21  4972 156_1 0.2 60 6 145 6  4972 156_1 1 46 14 145 NA  4973 157_1 0.2 75 9 128 6  4973 157_1 1 59 NA 158 NA  4979 158_1 0.2 46 9 131 NA  4979 158_1 1 37 5 219 8  5058 159_1 0.2 69 6 133 19  5058 159_1 1 51 14 NA NA  5071 160_1 0.2 55 8 98 NA  5071 160_1 1 39 7 136 34  5078 161_1 0.2 65 7 205 18  5078 161_1 1 51 10 306 31  5094 162_1 0.2 53 5 154 27  5094 162_1 1 34 8 300 65  5096 163_1 0.2 44 1 206 49  5096 163_1 1 36 6 316 NA  5100 164_1 0.2 34 3 220 NA  5100 164_1 1 30 3 227 32  5101 165_1 0.2 38 7 245 NA  5101 165_1 1 36 4 246 55  5218 166_1 0.2 45 4 240 NA  5218 166_1 1 36 6 280 44  5218 167_1 0.2 46 2 261 NA  5218 167_1 1 31 4 346 30  5224 168_1 0.2 39 3 377 40  5224 168_1 1 33 5 338 65  5224 169_1 0.2 37 4 313 NA  5224 169_1 1 3 2 308 3  5427 170_1 0.2 89 13 105 26  5427 170_1 1 117 35 124 NA  5434 171_1 0.2 51 5 164 10  5434 171_1 1 33 6 213 46  5785 172_1 0.2 46 5 210 NA  5785 172_1 1 38 4 342 NA  5786 173_1 0.2 54 4 292 61  5786 173_1 1 3 6 552 NA  6341 174_1 0.2 97 11 126 3  6341 174_1 1 90 33 NA NA  6694 175_1 0.2 44 4 226 NA  6694 175_1 1 35 4 296 NA  6695 176_1 0.2 32 7 297 87  6695 176_1 1 29 4 263 9  6958 177_1 0.2 58 7 244 76  6958 177_1 1 47 NA NA NA  7159 179_1 0.2 33 4 282 NA  7159 179_1 1 29 5 289 7  7159 178_1 0.2 43 5 248 NA  7159 178_1 1 32 4 258 NA  7720 180_1 0.2 75 6 144 36  7720 180_1 1 54 7 233 26  7724 181_1 0.2 72 6 177 20  7724 181_1 1 45 19 224 62  7725 182_1 0.2 65 5 139 37  7725 182_1 1 47 4 208 76  7725 183_1 0.2 103 13 140 2  7725 183_1 1 74 6 NA NA  7727 184_1 0.2 45 2 300 107  7727 184_1 1 35 2 272 16  8117 185_1 0.2 87 17 122 13  8117 185_1 1 63 17 175 NA  8118 186_1 0.2 40 5 368 105  8118 186_1 1 33 5 NA NA  8119 187_1 0.2 62 5 197 NA  8119 187_1 1 43 13 517 143  8120 188_1 0.2 96 10 136 41  8120 188_1 1 79 22 146 19  8571 189_1 0.2 53 11 204 NA  8571 189_1 1 49 24 298 15  8573 190_1 0.2 54 9 140 9  8573 190_1 1 50 10 267 4  8574 191_1 0.2 56 1 117 NA  8574 191_1 1 57 13 199 NA  8575 192_1 0.2 56 9 165 10  8575 192_1 1 54 13 246 NA  8576 193_1 0.2 56 6 185 7  8576 193_1 1 52 8 330 35  8585 194_1 0.2 47 2 302 NA  8585 194_1 1 39 7 NA NA  8819 195_1 0.2 62 10 155 10  8819 195_1 1 41 3 192 7  8820 196_1 0.2 55 12 237 69  8820 196_1 1 40 3 278 26  8887 197_1 0.2 69 15 301 59  8887 197_1 1 58 7 383 92  9150 198_1 0.2 49 6 NA NA  9150 198_1 1 43 3 365 38  9201 199_1 0.2 79 23 88 42  9201 199_1 1 64 24 140 22  9202 201_1 0.2 61 10 NA NA  9202 201_1 1 45 8 343 27  9202 200_1 0.2 47 3 287 76  9202 200_1 1 41 4 281 NA  9203 202_1 0.2 55 17 166 92  9203 202_1 1 40 5 297 54  9209 203_1 0.2 60 1 122 NA  9209 203_1 1 40 14 204 8  9210 204_1 0.2 43 2 216 NA  9210 204_1 1 37 3 409 NA  9210 205_1 0.2 45 8 187 NA  9210 205_1 1 37 22 336 18  9211 206_1 0.2 51 10 384 17  9211 206_1 1 42 3 381 35  9211 207_1 0.2 65 8 301 28  9211 207_1 1 50 5 272 53  9212  35_2 0.2 42 11 203 16  9212  35_2 1 44 18 335 NA  9212 208_1 0.2 64 5 147 58  9212 208_1 1 50 6 260 73  9213 209_1 0.2 57 7 NA NA  9213 209_1 1 49 4 346 31  9214 210_1 0.2 49 7 139 NA  9214 210_1 1 45 7 223 59 10832 211_1 0.2 70 6 147 10 10832 211_1 1 56 9 200 38 10837 212_1 0.2 59 9 146 46 10837 212_1 1 41 6 226 47 10838 213_1 0.2 50 8 247 69 10838 213_1 1 44 12 307 NA 10877 214_1 0.2 108 21 115 1 10877 214_1 1 92 37 88 32 11434 215_1 0.2 97 12 8 23 11434 215_1 1 80 26 111 11 11435 216_1 0.2 90 16 87 NA 11435 216_1 1 8 29 82 21 11436 217_1 0.2 87 6 83 11 11436 217_1 1 68 26 123 NA 11438 218_1 0.2 57 5 133 NA 11438 218_1 1 44 16 188 NA 11439 219_1 0.2 84 1 93 NA 11439 219_1 1 66 22 113 29 11464 220_1 0.2 67 9 209 51 11464 220_1 1 41 6 256 33 11507 221_1 0.2 59 6 237 NA 11507 221_1 1 40 63 320 NA 11508 222_1 0.2 53 7 195 NA 11508 222_1 1 48 12 302 NA 11511 223_1 0.2 41 3 210 6 11511 223_1 1 37 9 273 NA 11513 224_1 0.2 22 8 288 91 11513 224_1 1 26 5 360 46 11514 225_1 0.2 98 17 98 31 11514 225_1 1 68 16 129 11 11736 226_1 0.2 69 8 197 80 11736 226_1 1 55 7 329 66 12361 227_1 0.2 48 8 183 56 12361 227_1 1 37 4 193 46 12794 228_1 0.2 38 9 201 71 12794 228_1 1 32 2 362 48 12795 229_1 0.2 50 12 161 30 12795 229_1 1 34 7 301 35 12796 230_1 0.2 44 12 237 86 12796 230_1 1 32 3 379 106 12894 232_1 0.2 91 17 79 27 12894 232_1 1 66 10 99 24 12894 231_1 0.2 80 5 89 NA 12894 231_1 1 57 14 164 31 12895 234_1 0.2 88 11 75 32 12895 234_1 1 68 19 91 24 12895 233_1 0.2 57 5 199 37 12895 233_1 1 38 7 249 57 12896 235_1 0.2 72 3 176 9 12896 235_1 1 45 3 251 42 13223 236_1 0.2 40 3 267 66 13223 236_1 1 31 3 270 23 13224 238_1 0.2 33 3 265 NA 13224 238_1 1 28 4 265 6 13224 237_1 0.2 38 2 212 NA 13224 237_1 1 31 1 254 31 13225 239_1 0.2 42 5 317 113 13225 239_1 1 29 7 215 26 13226 240_1 0.2 38 7 223 NA 13226 240_1 1 32 5 232 16 15115 241_1 0.2 61 8 377 15 15115 241_1 1 41 3 377 43 15258 242_1 0.2 66 14 133 35 15258 242_1 1 55 10 170 17 15568 243_1 0.2 62 13 192 58 15568 243_1 1 41 11 309 5 15570 244_1 0.2 53 17 252 59 15570 244_1 1 44 5 332 52 15572 245_1 0.2 57 21 321 122 15572 245_1 1 4 7 407 77 15573 246_1 0.2 47 16 348 129 15573 246_1 1 40 7 410 69 15574 247_1 0.2 48 14 326 116 15574 247_1 1 44 8 411 36 15722 248_1 0.2 51 3 258 17 15722 248_1 1 36 3 230 NA 16597 249_1 0.2 66 19 111 39 16597 249_1 1 54 14 174 44 16603 250_1 0.2 67 26 89 31 16603 250_1 1 56 6 172 32 16730 251_1 0.2 36 5 354 41 16730 251_1 1 31 2 326 75 16849 252_1 0.2 74 17 188 81 16849 252_1 1 48 17 282 1 17089 253_1 0.2 70 17 98 37 17089 253_1 1 62 19 153 13 17401 254_1 0.2 42 6 209 83 17401 254_1 1 29 3 327 49 24290 255_1 0.2 106 13 105 36 24290 255_1 1 109 21 136 NA 24296 256_1 0.2 92 20 117 30 24296 256_1 1 93 15 138 21 24811 257_1 0.2 85 12 126 4 24811 257_1 1 74 12 137 7 25032 258_1 0.2 50 11 329 131 25032 258_1 1 39 5 411 53 25033 259_1 0.2 40 10 343 50 25033 259_1 1 31 3 483 84 25250 260_1 0.2 33 10 279 42 25250 260_1 1 33 4 338 65 25251 261_1 0.2 40 8 209 97 25251 261_1 1 34 3 370 57 25718 262_1 0.2 56 20 113 48 25718 262_1 1 45 8 198 65 25720 263_1 0.2 84 7 121 39 25720 263_1 1 72 11 88 10 25721 264_1 0.2 83 15 87 40 25721 264_1 1 84 22 NA NA 26331 265_1 0.2 93 5 88 38 26331 265_1 1 81 8 NA NA 27165 266_1 0.2 63 3 117 39 27165 266_1 1 46 9 174 15 27248 267_1 0.2 81 10 124 17 27248 267_1 1 59 10 190 112 29330 268_1 0.2 109 4 124 48 29330 268_1 1 98 28 114 35 29635 269_1 0.2 45 1 218 50 29635 269_1 1 33 9 267 NA 29635 270_1 0.2 55 5 225 41 29635 270_1 1 45 8 NA NA 29636 271_1 0.2 48 2 285 56 29636 271_1 1 40 7 359 99 29636 272_1 0.2 48 3 166 5 29636 272_1 1 35 8 293 40 29637 273_1 0.2 56 5 255 47 29637 273_1 1 46 4 300 105 29637 274_1 0.2 67 7 134 35 29637 274_1 1 54 7 234 19 29661 275_1 0.2 5 3 167 15 29661 275_1 1 42 11 251 NA 29661 276_1 0.2 54 5 127 17 29661 276_1 1 39 8 229 NA 29684 277_1 0.2 40 3 168 73 29684 277_1 1 31 13 NA NA 29684 278_1 0.2 46 7 179 2 29684 278_1 1 36 8 NA NA 30455 279_1 0.2 102 20 96 34 30455 279_1 1 86 22 118 23 30456 280_1 0.2 94 23 91 28 30456 280_1 1 83 18 134 36 30457 281_1 0.2 89 23 97 37 30457 281_1 1 94 23 106 39 30458 282_1 0.2 99 14 77 27 30458 282_1 1 103 17 96 20 30462 283_1 0.2 66 26 98 36 30462 283_1 1 56 14 129 13 30465 284_1 0.2 73 11 114 47 30465 284_1 1 57 10 197 63 30601 285_1 0.2 41 31 311 29 30601 285_1 1 30 16 373 40 30605 286_1 0.2 40 2 221 86 30605 286_1 1 33 6 375 NA 30609 287_1 0.2 43 3 267 65 30609 287_1 1 37 5 332 27 30610 288_1 0.2 46 6 253 79 30610 288_1 1 38 3 338 NA 30667 289_1 0.2 38 15 325 144 30667 289_1 1 36 3 461 68 30668 290_1 0.2 74 19 124 54 30668 290_1 1 58 14 183 20 30669 291_1 0.2 86 18 98 40 30669 291_1 1 78 12 133 26 30670 292_1 0.2 93 10 86 31 30670 292_1 1 94 16 127 22 30679 293_1 0.2 85 19 83 21 30679 293_1 1 87 21 113 23 30681 294_1 0.2 92 17 78 20 30681 294_1 1 100 19 86 22 30682 295_1 0.2 93 22 101 40 30682 295_1 1 94 33 101 8 30699 296_1 0.2 80 24 134 6 30699 296_1 1 47 21 232 36 30700 297_1 0.2 53 5 146 26 30700 297_1 1 32 8 NA NA 30700 298_1 0.2 47 4 221 NA 30700 298_1 1 38 0 294 NA 30701 299_1 0.2 49 4 140 NA 30701 299_1 1 23 NA NA NA 30701 300_1 0.2 50 9 163 19 30701 300_1 1 39 11 346 11 30702 301_1 0.2 66 9 116 36 30702 301_1 1 44 14 230 51 30711 302_1 0.2 41 14 288 120 30711 302_1 1 40 5 422 132 30714 303_1 0.2 45 9 355 94 30714 303_1 1 31 5 355 8 30715 305_1 0.2 39 4 292 56 30715 305_1 1 34 12 253 5 30715 304_1 0.2 50 13 263 87 30715 304_1 1 43 7 285 12 31630 306_1 0.2 92 32 134 48 31630 306_1 1 85 25 177 26 31632 307_1 0.2 94 24 92 32 31632 307_1 1 86 17 109 33 31633 308_1 0.2 92 18 78 13 31633 308_1 1 102 23 98 7 32755 310_1 0.2 47 12 220 40 32755 310_1 1 40 16 285 NA 32755 309_1 0.2 62 6 167 NA 32755 309_1 1 40 10 225 NA 32756 311_1 0.2 55 9 128 9 32756 311_1 1 56 NA 224 NA 33366 312_1 0.2 64 23 121 4 33366 312_1 1 56 10 137 1 33367 313_1 0.2 81 7 9 NA 33367 313_1 1 79 22 115 12 33368 314_1 0.2 70 4 103 NA 33368 314_1 1 57 15 157 NA 33369 315_1 0.2 73 12 87 20 33369 315_1 1 67 19 155 NA 33375 316_1 0.2 79 18 100 18 33375 316_1 1 51 14 159 39 33377 317_1 0.2 46 21 248 72 33377 317_1 1 41 9 313 NA 33378 318_1 0.2 38 17 273 63 33378 318_1 1 36 7 321 1 36606 319_1 0.2 79 10 154 21 36606 319_1 1 48 9 233 65 36607 320_1 0.2 60 9 157 18 36607 320_1 1 49 9 206 25 38092 321_1 0.2 51 10 221 59 38092 321_1 1 41 5 328 39 38297 322_1 0.2 43 9 298 31 38297 322_1 1 34 6 365 91 39173 323_1 0.2 98 8 119 27 39173 323_1 1 82 20 177 21 39174 324_1 0.2 89 8 139 24 39174 324_1 1 84 23 192 15 39175 325_1 0.2 93 18 167 13 39175 325_1 1 68 17 203 33 39176 326_1 0.2 79 12 185 83 39176 326_1 1 55 17 374 107 39228 327_1 0.2 75 12 151 29 39228 327_1 1 57 8 207 32 39230 328_1 0.2 65 11 176 19 39230 328_1 1 52 19 357 NA 39231 329_1 0.2 63 19 150 35 39231 329_1 1 46 6 257 43 39563 330_1 0.2 69 10 116 34 39563 330_1 1 56 11 196 NA 39808 331_1 0.2 40 8 201 17 39808 331_1 1 25 5 300 NA 39808 332_1 0.2 40 14 282 109 39808 332_1 1 33 7 404 81 39931 333_1 0.2 80 11 107 53 39931 333_1 1 70 16 112 26 41114 334_1 0.2 64 4 113 NA 41114 334_1 1 28 NA 179 NA 41444 335_1 0.2 57 17 165 39 41444 335_1 1 46 4 290 40 41445 336_1 0.2 51 2 134 NA 41445 336_1 1 42 15 238 NA 41446 337_1 0.2 63 1 108 NA 41446 337_1 1 56 14 151 22 41725 338_1 0.2 91 16 130 50 41725 338_1 1 75 23 154 27 41726 339_1 0.2 6 20 142 23 41726 339_1 1 55 14 193 NA 41728 340_1 0.2 60 16 137 23 41728 340_1 1 51 13 233 NA 42167 341_1 0.2 70 9 138 7 42167 341_1 1 51 11 182 20 42168 343_1 0.2 67 9 210 92 42168 343_1 1 52 6 193 NA 42168 342_1 0.2 51 6 183 NA 42168 342_1 1 46 10 275 14 42169 344_1 0.2 55 1 231 32 42169 344_1 1 35 3 NA NA 42169 345_1 0.2 55 7 164 41 42169 345_1 1 45 5 284 27 42287 346_1 0.2 66 7 144 32 42287 346_1 1 53 5 279 34 42289 347_1 0.2 75 20 125 10 42289 347_1 1 68 7 241 69 43452 348_1 0.2 62 12 231 92 43452 348_1 1 48 23 257 72 43453 349_1 0.2 52 11 142 41 43453 349_1 1 44 23 257 34 43562 350_1 0.2 50 13 148 35 43562 350_1 1 36 10 NA NA 43565 351_1 0.2 71 10 116 43 43565 351_1 1 60 11 154 37 43566 352_1 0.2 65 19 139 14 43566 352_1 1 44 8 255 23 43634 353_1 0.2 63 25 172 75 43634 353_1 1 51 22 214 NA 44180 355_1 0.2 60 6 165 8 44180 355_1 1 57 25 145 NA 44180 354_1 0.2 76 17 149 55 44180 354_1 1 48 10 240 29 44181 356_1 0.2 60 5 170 27 44181 356_1 1 43 15 154 55 44183 357_1 0.2 50 15 214 33 44183 357_1 1 37 17 196 19 44184 358_1 0.2 57 5 155 31 44184 358_1 1 47 10 257 94 44439 359_1 0.2 46 4 220 53 44439 359_1 1 45 2 347 52 44440 360_1 0.2 48 9 261 37 44440 360_1 1 44 6 NA NA 44440 361_1 0.2 43 5 218 46 44440 361_1 1 29 3 291 19 44441 362_1 0.2 50 5 192 60 44441 362_1 1 45 7 290 58 44441 363_1 0.2 45 10 185 51 44441 363_1 1 43 10 247 NA 44442 364_1 0.2 54 8 124 24 44442 364_1 1 39 5 271 54 44442 365_1 0.2 59 6 166 9 44442 365_1 1 44 8 313 47 44443 367_1 0.2 55 10 161 29 44443 367_1 1 40 7 314 67 44443 366_1 0.2 51 5 202 44 44443 366_1 1 41 10 300 31 44477 368_1 0.2 73 6 155 58 44477 368_1 1 52 3 362 141 44478 369_1 0.2 82 18 130 35 44478 369_1 1 58 11 228 66 44776 370_1 0.2 60 7 128 20 44776 370_1 1 46 5 274 NA 45216 371_1 0.2 50 10 149 33 45216 371_1 1 41 8 260 59 45217 372_1 0.2 59 7 132 45 45217 372_1 1 39 4 270 12 45217 373_1 0.2 47 3 167 52 45217 373_1 1 38 4 330 62 45218 374_1 0.2 51 9 189 27 45218 374_1 1 42 9 359 93 45246 375_1 0.2 61 8 175 29 45246 375_1 1 50 7 257 NA 45247 376_1 0.2 84 4 116 40 45247 376_1 1 74 10 144 NA 45248 378_1 0.2 61 10 226 2 45248 378_1 1 50 5 367 141 45248 377_1 0.2 74 11 138 29 45248 377_1 1 62 4 251 NA 45249 379_1 0.2 48 5 232 NA 45249 379_1 1 50 NA 312 NA 45249 380_1 0.2 54 4 203 16 45249 380_1 1 53 1 353 12 45250 381_1 0.2 48 6 230 25 45250 381_1 1 40 7 387 79 45250 382_1 0.2 60 7 153 30 45250 382_1 1 46 3 288 43 45258 383_1 0.2 46 4 211 NA 45258 383_1 1 34 6 307 29 45266 385_1 0.2 80 34 85 8 45266 385_1 1 55 13 128 25 45266 384_1 0.2 92 4 128 50 45266 384_1 1 79 12 108 23 45267 386_1 0.2 93 23 105 13 45267 386_1 1 80 23 139 14 45268 387_1 0.2 90 17 111 1 45268 387_1 1 109 9 122 44 45270 388_1 0.2 97 7 146 47 45270 388_1 1 88 9 113 22 45271 390_1 0.2 79 12 141 14 45271 390_1 1 58 14 197 38 45271 389_1 0.2 70 3 97 28 45271 389_1 1 53 6 150 26 45272 391_1 0.2 61 4 128 24 45272 391_1 1 55 14 208 39 45560 392_1 0.2 86 22 97 26 45560 392_1 1 71 19 125 18 45627 393_1 0.2 48 14 150 64 45627 393_1 1 39 1 209 35 45628 394_1 0.2 51 4 174 34 45628 394_1 1 44 8 309 30 45629 395_1 0.2 60 5 151 24 45629 395_1 1 48 7 297 43 45629 396_1 0.2 86 24 139 55 45629 396_1 1 64 13 203 38 45635 397_1 0.2 50 10 289 61 45635 397_1 1 46 2 401 56 45709 398_1 0.2 47 6 207 61 45709 398_1 1 49 6 233 NA 45709 399_1 0.2 56 6 206 13 45709 399_1 1 45 4 287 93 46215 400_1 0.2 78 14 122 13 46215 400_1 1 60 9 114 19 46256 401_1 0.2 62 7 164 56 46256 401_1 1 45 5 213 20 46257 404_1 0.2 44 4 207 44 46257 404_1 1 41 3 288 45 46257 402_1 0.2 48 5 197 57 46257 402_1 1 41 1 300 11 46257 403_1 0.2 51 4 265 50 46257 403_1 1 44 5 382 NA 46259 405_1 0.2 46 4 NA NA 46259 405_1 1 39 10 359 10 46260 406_1 0.2 52 9 153 63 46260 406_1 1 48 7 262 71 46263 407_1 0.2 52 9 148 9 46263 407_1 1 41 5 262 45 46264 408_1 0.2 5 17 269 72 46264 408_1 1 42 8 280 55 46392 409_1 0.2 38 10 359 91 46392 409_1 1 38 8 NA NA 46393 410_1 0.2 39 12 295 30 46393 410_1 1 32 12 NA NA 46420 411_1 0.2 75 10 69 3 46420 411_1 1 86 3 101 21 46505 412_1 0.2 65 11 97 7 46505 412_1 1 53 5 226 59 46505 413_1 0.2 74 16 124 19 46505 413_1 1 69 13 117 11 46506 414_1 0.2 75 7 149 17 46506 414_1 1 71 10 169 118 46507 415_1 0.2 86 31 119 36 46507 415_1 1 66 17 129 28 46508 416_1 0.2 86 22 87 22 46508 416_1 1 67 10 142 16 47364 417_1 0.2 49 2 166 22 47364 417_1 1 47 13 295 NA 47365 418_1 0.2 54 3 131 29 47365 418_1 1 41 3 230 42 48110 419_1 0.2 77 9 101 45 48110 419_1 1 58 8 178 68 48111 420_1 0.2 63 7 121 32 48111 420_1 1 51 2 238 59 48186 421_1 0.2 69 5 176 52 48186 421_1 1 44 12 307 62 48221 422_1 0.2 58 15 149 63 48221 422_1 1 39 6 235 50 48222 423_1 0.2 60 12 143 9 48222 423_1 1 43 10 209 57 49345  85 2 0.2 43 14 242 38 49345  85 2 1 37 5 275 NA 50282 424_1 0.2 75 20 138 19 50282 424_1 1 56 9 226 62 51241 426_1 0.2 61 6 144 NA 51241 426_1 1 46 9 264 44 51241 425_1 0.2 46 8 164 22 51241 425_1 1 44 4 244 35 51242 428_1 0.2 57 6 138 30 51242 428_1 1 48 7 290 39 51242 427_1 0.2 40 15 341 NA 51242 427_1 1 30 8 286 63 51244 429_1 0.2 46 5 184 25 51244 429_1 1 44 6 283 4 51245 430_1 0.2 47 7 203 9 51245 430_1 1 37 5 271 29 51358 431_1 0.2 51 7 265 10 51358 431_1 1 40 4 363 70 51358 432_1 0.2 60 4 202 51 51358 432_1 1 37 7 275 NA 51359 433_1 0.2 40 3 238 20 51359 433_1 1 32 3 NA NA 51359 434_1 0.2 39 6 424 83 51359 434_1 1 35 6 360 NA 51438 435_1 0.2 78 15 144 62 51438 435_1 1 60 14 201 27 51438 436_1 0.2 71 4 125 32 51438 436_1 1 54 6 205 71 51953 437_1 0.2 46 6 217 35 51953 437_1 1 37 4 277 52 52150 438_1 0.2 67 6 131 39 52150 438_1 1 53 13 177 NA 52549 439_1 0.2 56 5 162 31 52549 439_1 1 50 10 215 39 52550 440_1 0.2 69 13 137 40 52550 440_1 1 50 5 156 53 52551 441_1 0.2 66 3 132 8 52551 441_1 1 49 5 169 27 52579 442_1 0.2 38 7 280 60 52579 442_1 1 37 5 257 51 53012 443_1 0.2 79 10 197 61 53012 443_1 1 65 7 212 36 53013 445_1 0.2 64 6 211 13 53013 445_1 1 56 4 264 42 53013 444_1 0.2 68 11 137 33 53013 444_1 1 58 9 198 35 53014 446_1 0.2 59 6 125 NA 53014 446_1 1 47 3 216 22 53014 447_1 0.2 53 2 188 94 53014 447_1 1 51 10 192 47 54198 448_1 0.2 54 15 161 66 54198 448_1 1 48 11 243 NA 54199 449_1 0.2 63 12 166 20 54199 449_1 1 45 8 185 41 54232 450_1 0.2 84 17 112 67 54232 450_1 1 83 8 157 15 54233 451_1 0.2 67 14 118 44 54233 451_1 1 51 8 192 34 54235 452_1 0.2 50 3 162 NA 54235 452_1 1 42 7 190 NA 54236 453_1 0.2 47 21 234 17 54236 453_1 1 42 5 295 NA 54238 454_1 0.2 76 14 85 NA 54238 454_1 1 48 12 162 NA 54239 455_1 0.2 62 6 132 69 54239 455_1 1 46 7 149 57 54609 456_1 0.2 66 10 130 57 54609 456_1 1 56 11 141 60 54924 457_1 0.2 78 3 137 29 54924 457_1 1 61 4 178 25

Example 4—Activity of Oligonucleotides Targeting the SNHG14 Transcript in the Region Antisense to to the UBE3A Pre-mRNA

Oligonucleotides targeting position 55337-136214 of SEQ ID NO: 1 were tested in patient derived human neuronal cell cultures (see protocol in “Materials and methods” section). The oligonucleotides ability to reduce the SNHG14 transcript in the region downstream of SNORD109B (also termed UBE3A suppressor or UBE3A-SUP in the data table). Furthermore, the ability to induce UBE3A mRNA re-expression was analyzed.

The oligonucleotides were screened according to the protocol for screening oligonucleotides in human neuronal cell cultures described in the section “Materials and methods”—“Screening oligonucleotides in human neuronal cell cultures—96 well system”.

The results are shown in table 7.

TABLE 7 Oligonucleotide activity in patient derived human neuronal cell cultures. Start SEQ CMP ID Conc % of Mock % of Mock ID NO 1 NO μM UBE3A-SUP sd UBE3A sd  55337 458_1 0.2 64 0 177 6  55337 458_1 1 50 10 233 9  55338 459_1 0.2 48 1 186 6  55338 459_1 1 44 9 213 NA  59565 460_1 0.2 66 4 110 24  59565 460_1 1 66 9 131 23  59574 461_1 0.2 56 5 162 19  59574 461_1 1 45 13 149 6  59575 462_1 0.2 56 7 114 84  59575 462_1 1 39 11 101 13  59576 463_1 0.2 82 19 52 NA  59576 463_1 1 65 5 95 18  60012 464_1 0.2 47 5 129 71  60012 464_1 1 41 3 160 64  60298 465_1 0.2 49 7 206 95  60298 465_1 1 37 9 222 44  60448 466_1 0.2 47 7 130 NA  60448 466_1 1 33 8 167 31  60821 467_1 0.2 87 1 73 NA  60821 467_1 1 62 8 101 3  61925 468_1 0.2 108 19 105 19  61925 468_1 1 95 17 101 19  62287 469_1 0.2 62 8 180 57  62287 469_1 1 48 5 196 38  62422 470_1 0.2 71 2 130 20  62422 470_1 1 57 9 116 18  62443 471_1 0.2 51 2 NA NA  62443 471_1 1 43 2 160 34  64113 472_1 0.2 95 4 83 22  64113 472_1 1 76 14 74 36  64461 473_1 0.2 79 23 141 22  64461 473_1 1 59 12 279 53  64462 474_1 0.2 80 12 138 3  64462 474_1 1 84 15 202 3  65272 475_1 0.2 77 3 104 2  65272 475_1 1 75 23 113 10  66840 476_1 0.2 67 5 86 5  66840 476_1 1 72 10 100 12  67426 477_1 0.2 62 15 101 8  67426 477_1 1 65 13 170 52  68194 478_1 0.2 53 10 109 6  68194 478_1 1 59 4 178 7  68328 479_1 0.2 74 6 94 2  68328 479_1 1 79 6 111 38  68805 480_1 0.2 58 15 157 63  68805 480_1 1 49 2 190 26  68921 481_1 0.2 58 7 210 58  68921 481_1 1 55 10 281 NA  70133 482_1 0.2 50 9 149 6  70133 482_1 1 54 8 247 41  72377 483_1 0.2 44 2 143 NA  72377 483_1 1 52 6 195 37  72378 484_1 0.2 47 12 111 8  72378 484_1 1 56 3 201 NA  72826 485_1 0.2 54 2 116 0  72826 485_1 1 64 13 172 1  72861 486_1 0.2 52 9 93 6  72861 486_1 1 54 6 167 16  72887 487_1 0.2 55 3 128 5  72887 487_1 1 59 4 193 24  73474 488_1 0.2 55 10 132 20  73474 488_1 1 55 5 202 56  73992 489_1 0.2 60 7 146 17  73992 489_1 1 67 7 197 31  74791 490_1 0.2 42 5 167 65  74791 490_1 1 46 6 277 19  74851 491_1 0.2 69 14 78 1  74851 491_1 1 73 6 114 11  74853 492_1 0.2 64 6 84 1  74853 492_1 1 68 5 136 25  75840 493_1 0.2 40 10 90 6  75840 493_1 1 61 8 155 32  75841 494_1 0.2 65 10 131 30  75841 494_1 1 57 4 119 16  76238 495_1 0.2 70 9 109 41  76238 495_1 1 50 8 156 22  76254 496_1 0.2 67 13 134 34  76254 496_1 1 55 7 201 NA  76811 497_1 0.2 83 7 134 41  76811 497_1 1 77 8 148 32  77114 498_1 0.2 59 2 128 13  77114 498_1 1 64 10 206 NA  80468 499_1 0.2 55 2 105 34  80468 499_1 1 61 6 151 42  81047 500_1 0.2 103 17 80 6  81047 500_1 1 143 25 122 7  82233 501_1 0.2 57 NA 104 NA  82233 501_1 1 6 3 199 39  84166 502_1 0.2 49 6 89 0  84166 502_1 1 57 5 115 NA  85392 503_1 0.2 61 6 90 14  85392 503_1 1 62 8 118 15  86974 504_1 0.2 73 7 82 4  86974 504_1 1 79 3 104 19  87728 505_1 0.2 79 14 76 2  87728 505_1 1 80 19 97 35  87810 506_1 0.2 69 9 101 20  87810 506_1 1 73 6 155 2  88417 507_1 0.2 45 NA 116 3  88417 507_1 1 61 14 168 6  88991 508_1 0.2 51 6 113 20  88991 508_1 1 59 2 154 31  90228 509_1 0.2 65 6 76 10  90228 509_1 1 62 7 118 4  90474 510_1 0.2 71 7 83 14  90474 510_1 1 81 3 125 NA  91625 511_1 0.2 57 17 105 3  91625 511_1 1 65 11 150 NA  91885 512_1 0.2 57 5 105 1  91885 512_1 1 66 7 155 30  92976 513_1 0.2 67 6 136 44  92976 513_1 1 68 11 138 38  94304 514_1 0.2 81 11 110 7  94304 514_1 1 87 6 153 28  94528 515_1 0.2 48 5 128 6  94528 515_1 1 55 3 191 25  95653 516_1 0.2 57 3 108 7  95653 516_1 1 62 3 131 16  96751 517_1 0.2 63 9 90 19  96751 517_1 1 62 4 106 NA  97636 518_1 0.2 49 5 107 14  97636 518_1 1 44 9 137 NA  98480 519_1 0.2 55 1 106 NA  98480 519_1 1 5 5 112 23  98481 520_1 0.2 55 2 116 6  98481 520_1 1 62 4 129 6  99646 521_1 0.2 74 10 105 1  99646 521_1 1 87 13 119 27 100334 522_1 0.2 49 7 157 28 100334 522_1 1 57 2 120 37 101110 523_1 0.2 51 10 96 10 101110 523_1 1 72 14 114 25 101898 524_1 0.2 85 11 79 3 101898 524_1 1 93 21 92 46 102558 525_1 0.2 82 9 104 8 102558 525_1 1 86 18 104 30 103589 526_1 0.2 85 17 114 14 103589 526_1 1 94 39 126 6 104309 527_1 0.2 63 11 148 2 104309 527_1 1 70 26 155 NA 105686 528_1 0.2 66 11 91 24 105686 528_1 1 66 14 140 36 107972 529_1 0.2 84 15 109 15 107972 529_1 1 94 14 127 24 108257 530_1 0.2 63 7 114 19 108257 530_1 1 67 12 141 40 109407 531_1 0.2 84 24 87 16 109407 531_1 1 82 11 127 26 110210 532_1 0.2 72 12 91 14 110210 532_1 1 80 14 122 40 110768 533_1 0.2 67 8 126 16 110768 533_1 1 87 21 176 45 111811 534_1 0.2 77 2 98 17 111811 534_1 1 74 6 143 14 111812 535_1 0.2 64 4 97 0 111812 535_1 1 77 3 136 37 112149 536_1 0.2 73 2 63 2 112149 536_1 1 77 18 127 36 112150 537_1 0.2 76 6 78 8 112150 537_1 1 90 29 91 11 112945 538_1 0.2 69 4 121 2 112945 538_1 1 83 14 102 39 113533 539_1 0.2 95 17 85 2 113533 539_1 1 91 27 87 17 114274 540_1 0.2 89 11 103 17 114274 540_1 1 87 26 132 20 114495 541_1 0.2 76 5 88 1 114495 541_1 1 83 15 120 6 114831 542_1 0.2 59 3 76 4 114831 542_1 1 74 3 104 4 115355 543_1 0.2 66 8 91 9 115355 543_1 1 74 16 110 NA 116105 544_1 0.2 55 12 77 NA 116105 544_1 1 74 6 110 8 116106 545_1 0.2 58 18 96 9 116106 545_1 1 66 8 130 10 117096 546_1 0.2 69 9 118 20 117096 546_1 1 65 4 146 NA 117189 547_1 0.2 69 6 98 9 117189 547_1 1 74 11 146 25 117476 548_1 0.2 59 4 8 5 117476 548_1 1 65 3 104 10 118293 549_1 0.2 55 8 92 3 118293 549_1 1 66 10 105 24 118294 550_1 0.2 55 18 90 4 118294 550_1 1 72 2 119 5 118756 551_1 0.2 60 13 86 18 118756 551_1 1 88 24 120 26 119621 552_1 0.2 77 21 117 4 119621 552_1 1 102 19 146 NA 120655 553_1 0.2 55 9 124 19 120655 553_1 1 57 7 185 14 123733 554_1 0.2 74 6 87 14 123733 554_1 1 77 4 127 4 124163 555_1 0.2 89 12 117 46 124163 555_1 1 67 20 152 13 125512 556_1 0.2 70 5 114 26 125512 556_1 1 69 11 119 47 126882 557_1 0.2 78 15 106 8 126882 557_1 1 84 10 113 33 127105 558_1 0.2 71 7 91 13 127105 558_1 1 68 5 108 28 127809 559_1 0.2 59 4 74 NA 127809 559_1 1 58 7 101 26 129020 560_1 0.2 82 11 103 39 129020 560_1 1 77 9 103 27 129205 561_1 0.2 75 24 78 16 129205 561_1 1 89 1 102 23 129928 562_1 0.2 57 0 98 21 129928 562_1 1 63 9 107 18 130020 563_1 0.2 65 5 85 9 130020 563_1 1 65 3 145 12 130884 564_1 0.2 81 24 117 31 130884 564_1 1 83 4 139 17 130886 565_1 0.2 80 8 103 13 130886 565_1 1 69 7 122 11 131404 566_1 0.2 79 4 85 3 131404 566_1 1 80 7 116 24 132514 567_1 0.2 71 8 98 28 132514 567_1 1 69 9 97 29 133367 568_1 0.2 78 9 88 16 133367 568_1 1 91 17 88 32 136198 569_1 0.2 88 5 87 2 136198 569_1 1 81 6 109 35

Example 5—Activity of Oligonucleotides Targeting the SNHG14 Transcript in the Region Downstream of SNORD109B and Upstream of the Region Antisense to to the UBE3A Pre-mRNA

Oligonucleotides targeting position 5224-51257 of SEQ ID NO: 1 were tested in patient derived human neuronal cell cultures (see protocol in “Materials and methods” section). The oligonucleotides ability to reduce the SNHG14 transcript in the region downstream of SNORD109B (also termed UBE3A suppressor or UBE3A-SUP in the data table. Furthermore, the ability to induce UBE3A mRNA re-expression was analyzed.

The oligonucleotides were screened according to the protocol for screening oligonucleotides in human neuronal cell cultures described in the section “Materials and methods” “Screening oligonucleotides in human neuronal cell cultures—96 well system” with the following modifications:

UBE3a-Sense Primer

Using commercially available primers and probe from ThermoFisher: Hs00166580_m1 amplifying a 94 bp sequence in position 838 of refseq ID NM_000462.3.

Each plate include PBS controls (instead on a non-targeting ologinucleotide) and a positive control oligonucleotide CMP ID NO: 2711, resulting in up-regulation of UBE3A mRNA. The additional control oligonucleotides were not included.

Data are presented as average % expression relative to PBS controls across all plates and normalized to the positive control oligonucleotide to manage plate to plate variation in efficacy levels. The results are shown in table 8.

TABLE 8 Oligonucleotide activity in patient derived human neuronal cell cultures. Start SEQ CMP ID Conc % of Mock % of Mock ID NO 1 NO μM UBE3A-SUP sd UBE3A sd  5224 169_2 7.5 μM 49 4 209 9  5224 169_3 7.5 μM 47 5 282 5  5224 169_4 7.5 μM 57 14 202 12  5224 169_5 7.5 μM 84 36 148 4  5224 169_6 7.5 μM 42 1 285 16  5224 169_7 7.5 μM 52 6 233 27  5224 169_8 7.5 μM 51 7 278 11  5224 169_9 7.5 μM 51 4 228 20  5224 169_10 7.5 μM 78 17 143 5  5224 169_11 7.5 μM 74 15 146 2  5224 169_12 7.5 μM 47 1 277 26  5224 169_13 7.5 μM 56 23 244 42  5224 169_14 7.5 μM 74 16 141 1  5224 169_15 7.5 μM 95 32 122 13  5224 169_16 7.5 μM 44 4 276 23  5224 169_17 7.5 μM 85 5 118 5  5224 169_18 7.5 μM 75 18 131 4  5224 169_19 7.5 μM 95 18 126 11  5224 169_20 7.5 μM 61 12 169 20  5224 169_21 7.5 μM 79 18 156 3  5224 169_22 7.5 μM 63 14 173 16  5224 169_23 7.5 μM 43 2 233 27  5224 169_24 7.5 μM 56 1 183 9  5224 169_25 7.5 μM 48 0 220 24  5224 169_26 7.5 μM 41 1 244 39  5224 169_27 7.5 μM 55 16 260 42  5224 169_28 7.5 μM 48 1 265 65  5224 169_29 7.5 μM 56 2 197 18  5224 169_30 7.5 μM 57 12 189 12  5224 169_31 7.5 μM 53 4 196 9  5224 169_32 7.5 μM 50 1 220 3  5224 169_33 7.5 μM 64 19 227 8  5224 169_34 7.5 μM 58 4 193 10  5224 169_35 7.5 μM 45 2 229 3  5224 169_36 7.5 μM 44 6 262 14  5224 169_37 7.5 μM 55 2 180 21  5224 169_38 7.5 μM 75 22 158 13  5224 169_39 7.5 μM 76 15 159 17  5224 169_40 7.5 μM 60 18 232 31  5224 169_41 7.5 μM 46 3 230 10  5224 169_42 7.5 μM 47 3 240 11  5224 169_43 7.5 μM 48 9 273 30  5224 169_44 7.5 μM 83 32 196 11  5224 169_45 7.5 μM 69 4 185 20  5224 169_46 7.5 μM 45 9 256 3  5224 169_47 7.5 μM 41 2 304 4  5224 169_48 7.5 μM 44 1 260 16  5224 169_49 7.5 μM 38 1 245 32  5224 169_50 7.5 μM 35 2 314 28  5224 169_51 7.5 μM 41 5 281 5  5224 169_52 7.5 μM 36 1 282 1  5224 169_53 7.5 μM 38 7 301 7  5224 169_54 7.5 μM 36 3 304 6  5224 169_55 7.5 μM 52 5 246 23  5224 169_56 7.5 μM 33 15 302 15  5224 169_57 7.5 μM 34 16 273 16  5784 570_1 7.5 μM 47 0 274 7  5784 570_2 7.5 μM 47 8 232 8  5784 570_3 7.5 μM 55 25 280 54  5784 570_4 7.5 μM 61 1 235 54  5784 570_5 7.5 μM 72 10 198 30  5784 570_6 7.5 μM 66 8 244 50  5784 570_7 7.5 μM 42 1 284 13  5784 570_8 7.5 μM 43 6 257 11  5784 570_9 7.5 μM 32 9 242 30  5785 571_1 7.5 μM 40 1 269 35  5785 571_2 7.5 μM 42 3 187 6  5785 571_3 7.5 μM 46 6 242 8  5785 571_4 7.5 μM 37 4 282 19  5785 571_5 7.5 μM 48 16 296 2  5785 571_6 7.5 μM 37 6 274 10  5785 571_7 7.5 μM 39 1 260 8  5785 571_8 7.5 μM 35 1 252 3  5785 571_9 7.5 μM 30 5 297 10  5786 572_1 7.5 μM 34 4 279 29  5786 572_2 7.5 μM 63 10 152 4  5786 572_3 7.5 μM 39 0 280 42  5786 572_4 7.5 μM 40 1 283 14  5786 572_5 7.5 μM 38 6 310 11  5786 572_6 7.5 μM 33 1 316 18  5786 572_7 7.5 μM 35 1 318 11  5786 572_8 7.5 μM 47 9 310 19  5786 572_9 7.5 μM 31 7 321 12  8116 573_1 7.5 μM 39 8 316 28  8116 573_2 7.5 μM 49 15 305 41  8116 573_3 7.5 μM 46 13 308 3  8116 573_4 7.5 μM 39 3 332 6  8116 573_5 7.5 μM 34 6 278 12  8116 573_6 7.5 μM 42 1 285 10  8116 573_7 7.5 μM 38 0 289 33  8116 573_8 7.5 μM 40 4 311 20  8116 573_9 7.5 μM 57 9 315 5  8117 574_1 7.5 μM 40 2 291 35  8117 574_2 7.5 μM 42 3 343 18  8117 574_3 7.5 μM 36 6 325 8  8117 574_4 7.5 μM 38 1 279 15  8117 574_5 7.5 μM 42 6 308 10  8117 574_6 7.5 μM 47 8 340 11  8117 574_7 7.5 μM 43 0 308 42  8117 574_8 7.5 μM 44 6 268 10  8117 574_9 7.5 μM 41 8 241 22  8118 575_1 7.5 μM 47 0 198 28  8118 575_2 7.5 μM 83 26 253 31  8118 575_3 7.5 μM 48 4 348 5  8118 575_4 7.5 μM 37 2 269 7  8118 575_5 7.5 μM 43 6 258 17  8118 575_6 7.5 μM 50 6 286 3  8118 575_7 7.5 μM 37 2 331 30  8118 575_8 7.5 μM 47 7 264 1  8118 575_9 7.5 μM 64 23 243 3  8119 576_1 7.5 μM 47 1 272 14  8119 576_2 7.5 μM 109 31 119 3  8119 576_3 7.5 μM 36 3 287 6  8119 576_4 7.5 μM 35 3 285 23  8119 576_5 7.5 μM 49 10 222 1  8119 576_6 7.5 μM 79 12 132 10  8119 576_7 7.5 μM 76 4 132 3  8119 576_8 7.5 μM 62 1 147 5  8119 576_9 7.5 μM 43 3 230 5  8120 577_1 7.5 μM 57 3 158 15  8120 577_2 7.5 μM 39 4 279 60  8120 577_3 7.5 μM 38 1 290 68  8120 577_4 7.5 μM 77 11 148 11  8120 577_5 7.5 μM 31 6 272 36  8120 577_6 7.5 μM 38 8 228 32  8120 577_7 7.5 μM 40 8 246 39  8120 577_8 7.5 μM 43 11 256 26  8120 577_9 7.5 μM 85 32 109 6  8584 578_1 7.5 μM 57 7 199 7  8584 578_2 7.5 μM 40 5 263 3  8584 578_3 7.5 μM 40 2 289 23  8584 578_4 7.5 μM 43 8 199 16  8584 578_5 7.5 μM 42 1 256 15  8584 578_6 7.5 μM 42 6 241 10  8584 578_7 7.5 μM 42 5 329 20  8584 578_8 7.5 μM 49 7 271 13  8584 578_9 7.5 μM 45 3 222 3  8585 579_1 7.5 μM 45 0 208 8  8585 579_2 7.5 μM 51 4 226 6  8585 579_3 7.5 μM 54 5 178 8  8585 579_4 7.5 μM 41 4 328 13  8585 579_5 7.5 μM 50 5 272 3  8585 579_6 7.5 μM 86 12 161 0  8585 579_7 7.5 μM 72 5 155 15  8585 579_8 7.5 μM 57 3 230 14  8585 579_9 7.5 μM 83 0 123 1  8586 580_1 7.5 μM 37 2 313 13  8586 580_2 7.5 μM 43 1 266 3  8586 580_3 7.5 μM 42 5 303 5  8586 580_4 7.5 μM 57 4 225 26  8586 580_5 7.5 μM 51 4 228 35  8586 580_6 7.5 μM 44 4 253 15  8586 580_7 7.5 μM 50 1 241 10  8586 580_8 7.5 μM 44 0 227 26  8586 580_9 7.5 μM 31 5 323 31  8587 581_1 7.5 μM 50 6 223 30  8587 581_2 7.5 μM 66 7 199 19  8587 581_3 7.5 μM 56 8 197 9  8587 581_4 7.5 μM 57 12 270 24  8587 581_5 7.5 μM 51 12 259 12  8587 581_6 7.5 μM 39 4 282 2  8587 581_7 7.5 μM 38 11 263 5  8587 581_8 7.5 μM 45 10 203 19  8587 581_9 7.5 μM 43 2 234 10  9209 582_1 7.5 μM 61 7 225 7  9209 582_2 7.5 μM 46 9 341 36  9209 582_3 7.5 μM 44 9 306 38  9209 582_4 7.5 μM 43 1 249 5  9209 582_5 7.5 μM 33 16 306 6  9209 582_6 7.5 μM 37 8 329 19  9209 582_7 7.5 μM 44 9 289 4  9209 582_8 7.5 μM 39 3 314 20  9209 582_9 7.5 μM 41 4 299 25  9210 583_1 7.5 μM 43 5 319 25  9210 583_2 7.5 μM 53 9 352 5  9210 583_3 7.5 μM 42 2 362 42  9210 583_4 7.5 μM 46 5 225 13  9210 583_5 7.5 μM 39 6 343 21  9210 583_6 7.5 μM 44 9 298 8  9210 583_7 7.5 μM 37 5 332 9  9210 583_8 7.5 μM 42 6 343 25  9210 583_9 7.5 μM 36 2 341 9  9211 584_1 7.5 μM 45 5 343 39  9211 584_2 7.5 μM 42 2 298 22  9211 584_3 7.5 μM 44 10 321 2  9211 584_4 7.5 μM 50 1 299 5  9211 584_5 7.5 μM 44 1 319 25  9211 584_6 7.5 μM 50 6 323 13  9211 584_7 7.5 μM 42 4 316 27  9211 584_8 7.5 μM 53 3 217 11  9212 208_2 7.5 μM 44 7 312 26  9212 208_3 7.5 μM 38 2 331 21  9212 208_4 7.5 μM 47 3 353 11  9212 208_5 7.5 μM 54 11 348 14  9212 208_6 7.5 μM 51 12 310 8  9212 208_7 7.5 μM 60 9 224 11  9213 209_2 7.5 μM 44 12 242 21  9213 209_3 7.5 μM 37 12 335 12  9213 209_4 7.5 μM 55 7 350 2  9213 209_5 7.5 μM 47 7 337 19  9213 209_6 7.5 μM 51 8 300 19  9213 209_7 7.5 μM 47 15 342 23  9213 209_8 7.5 μM 45 12 289 5  9213 209_9 7.5 μM 41 1 368 37  9213 209_10 7.5 μM 40 4 315 1 11511 585_1 7.5 μM 41 7 350 12 11511 585_2 7.5 μM 44 4 233 7 11511 585_3 7.5 μM 40 8 310 31 11511 585_4 7.5 μM 33 8 324 41 11511 585_5 7.5 μM 29 3 314 23 11511 585_6 7.5 μM 38 4 332 15 11511 585_7 7.5 μM 30 2 315 15 11511 585_8 7.5 μM 36 11 328 37 11511 585_9 7.5 μM 39 5 303 49 11512 586_1 7.5 μM 60 3 236 5 11512 586_2 7.5 μM 40 9 282 53 11512 586_3 7.5 μM 36 1 279 11 11512 586_4 7.5 μM 34 3 288 21 11512 586_5 7.5 μM 30 1 270 4 11512 586_6 7.5 μM 29 5 269 24 11512 586_7 7.5 μM 33 4 263 6 11512 586_8 7.5 μM 32 4 270 4 11512 586_9 7.5 μM 33 5 310 48 11513 587_1 7.5 μM 45 2 237 34 11513 587_2 7.5 μM 44 3 307 4 11513 587_3 7.5 μM 37 1 285 24 11513 587_4 7.5 μM 44 1 252 41 11513 587_5 7.5 μM 51 7 220 29 11513 587_6 7.5 μM 41 2 262 35 11513 587_7 7.5 μM 39 7 280 21 11513 587_8 7.5 μM 48 9 230 11 11513 587_9 7.5 μM 41 5 270 9 11514 588_1 7.5 μM 54 9 204 25 11514 588_2 7.5 μM 98 5 143 4 11514 588_3 7.5 μM 55 9 180 1 11514 588_4 7.5 μM 113 24 109 17 11514 588_5 7.5 μM 66 26 150 5 11514 588_6 7.5 μM 74 1 131 1 11514 588_7 7.5 μM 79 4 140 9 11514 588_8 7.5 μM 49 2 235 2 11514 588_9 7.5 μM 51 10 281 2 11515 589_1 7.5 μM 61 2 154 9 11515 589_2 7.5 μM 70 9 126 12 11515 589_3 7.5 μM 53 3 212 32 11515 589_4 7.5 μM 93 14 108 14 11515 589_5 7.5 μM 69 11 191 7 11515 589_6 7.5 μM 53 9 183 20 11515 589_7 7.5 μM 45 8 257 4 11515 589_8 7.5 μM 35 5 213 5 11515 589_9 7.5 μM 41 2 290 22 13223 236_2 7.5 μM 39 6 286 21 13223 236_3 7.5 μM 32 10 256 29 13223 236_4 7.5 μM 37 5 285 12 13223 236_5 7.5 μM 33 8 280 19 13223 236_6 7.5 μM 40 16 295 7 13223 236_7 7.5 μM 45 10 254 50 13223 236_8 7.5 μM 41 22 306 50 13223 236_9 7.5 μM 32 11 292 47 13223 236_10 7.5 μM 31 10 307 3 13223 236_11 7.5 μM 52 32 198 29 13223 236_12 7.5 μM 31 7 261 18 13223 236_13 7.5 μM 34 3 279 32 13223 236_14 7.5 μM 38 0 285 75 13223 236_15 7.5 μM 40 17 307 53 13223 236_16 7.5 μM 41 6 321 30 13224 237_2 7.5 μM 49 18 251 38 13224 237_3 7.5 μM 53 14 236 33 13224 237_4 7.5 μM 39 0 283 26 13224 237_5 7.5 μM 43 2 243 2 13224 237_6 7.5 μM 39 10 265 48 13224 237_7 7.5 μM 50 3 302 19 13224 237_8 7.5 μM 46 7 327 43 13224 237_9 7.5 μM 38 9 287 12 13224 237_10 7.5 μM 35 6 248 35 13224 237_11 7.5 μM 41 1 259 24 13224 237_12 7.5 μM 33 6 303 35 13224 237_13 7.5 μM 26 4 265 53 13224 237_14 7.5 μM 30 8 321 15 13224 237_15 7.5 μM 33 11 315 24 13224 237_16 7.5 μM 36 11 292 19 13225 239_2 7.5 μM 35 16 291 30 13225 239_3 7.5 μM 40 15 311 42 13225 239_4 7.5 μM 81 6 144 16 13225 239_5 7.5 μM 90 16 127 11 13225 239_6 7.5 μM 49 29 282 3 13225 239_7 7.5 μM 35 4 296 23 13225 239_8 7.5 μM 40 1 292 48 13225 239_9 7.5 μM 36 1 318 44 13225 239_10 7.5 μM 49 NA 304 NA 13225 239_11 7.5 μM 45 NA 258 NA 13225 239_12 7.5 μM 43 1 285 1 13225 239_13 7.5 μM 31 1 308 31 13225 239_14 7.5 μM 41 8 253 6 13225 239_15 7.5 μM 28 3 291 16 13225 239_16 7.5 μM 29 3 314 14 13226 590_1 7.5 μM 34 1 283 18 13226 590_2 7.5 μM 49 7 213 17 13226 590_3 7.5 μM 40 1 274 51 13226 590_4 7.5 μM 36 1 300 2 13226 590_5 7.5 μM 37 3 280 36 13226 590_6 7.5 μM 38 2 204 17 13226 590_7 7.5 μM 38 5 245 16 13226 590_8 7.5 μM 30 6 219 34 13226 590_9 7.5 μM 33 1 269 2 13226 590_10 7.5 μM 33 2 258 49 13226 590_11 7.5 μM 48 17 297 31 13226 590_12 7.5 μM 33 4 317 65 13226 590_13 7.5 μM 35 7 337 43 13226 590_14 7.5 μM 25 1 306 22 13226 590_15 7.5 μM 30 5 299 2 15113 591_1 7.5 μM 43 3 313 14 15113 591_2 7.5 μM 52 2 295 24 15114 592_1 7.5 μM 53 2 232 17 15114 592_2 7.5 μM 39 1 309 23 15114 592_3 7.5 μM 46 1 278 12 15114 592_4 7.5 μM 36 1 328 13 15114 592_5 7.5 μM 49 9 295 40 15114 592_6 7.5 μM 46 3 297 10 15114 592_7 7.5 μM 75 21 160 23 15114 592_8 7.5 μM 41 10 325 23 15114 592_9 7.5 μM 55 15 265 3 15115 241_2 7.5 μM 66 18 168 2 15115 241_3 7.5 μM 51 15 265 11 15115 241_4 7.5 μM 49 4 239 7 15115 241_5 7.5 μM 52 11 314 20 15115 241_6 7.5 μM 41 13 307 7 15115 241_7 7.5 μM 38 6 344 33 15115 241_8 7.5 μM 39 10 329 9 15115 241_9 7.5 μM 50 11 321 32 15115 241_10 7.5 μM 48 9 316 1 15563 593_1 7.5 μM 38 10 282 14 15563 593_2 7.5 μM 31 5 279 16 15563 593_3 7.5 μM 34 7 281 16 15563 593_4 7.5 μM 32 16 318 2 15563 594_1 7.5 μM 40 2 320 21 15563 594_2 7.5 μM 54 7 237 14 15563 594_3 7.5 μM 35 6 300 45 15563 594_4 7.5 μM 37 7 254 6 15564 596_1 7.5 μM 47 7 225 35 15564 596_2 7.5 μM 49 2 184 14 15564 596_3 7.5 μM 34 8 271 18 15564 596_4 7.5 μM 45 8 277 29 15564 595_1 7.5 μM 42 4 254 6 15564 595_2 7.5 μM 36 9 277 35 15564 595_3 7.5 μM 40 8 295 31 15564 595_4 7.5 μM 45 5 173 20 15566 597_1 7.5 μM 48 6 296 22 15566 597_2 7.5 μM 44 12 293 8 15566 597_3 7.5 μM 41 6 318 23 15566 597_4 7.5 μM 60 9 340 72 15567 38_3 7.5 μM 41 3 306 14 15567 38_4 7.5 μM 45 1 303 48 15567 38_5 7.5 μM 39 15 292 28 15567 38_6 7.5 μM 46 12 261 40 15567 598_1 7.5 μM 42 2 257 31 15567 598_2 7.5 μM 41 12 272 46 15567 598_3 7.5 μM 54 9 281 29 15567 598_4 7.5 μM 45 8 307 6 15568 599_1 7.5 μM 47 3 326 68 15568 599_2 7.5 μM 60 14 307 30 15568 599_3 7.5 μM 50 8 274 24 15568 599_4 7.5 μM 45 6 250 12 15568 600_1 7.5 μM 37 6 251 1 15568 600_2 7.5 μM 45 11 267 15 15568 600_3 7.5 μM 44 5 278 1 15568 600_4 7.5 μM 41 10 265 5 15569 601_1 7.5 μM 42 12 271 18 15569 601_2 7.5 μM 38 6 269 24 15569 601_3 7.5 μM 39 4 260 34 15569 601_4 7.5 μM 56 8 146 1 15570 244_2 7.5 μM 46 1 338 6 15570 244_3 7.5 μM 47 0 275 47 15570 244_4 7.5 μM 47 8 281 67 15570 244_5 7.5 μM 41 8 258 52 15570 39_2 7.5 μM 53 4 339 25 15570 39_3 7.5 μM 65 5 200 17 15570 39_4 7.5 μM 47 7 321 6 15570 39_5 7.5 μM 46 3 289 20 15571 602_1 7.5 μM 34 5 278 29 15571 602_2 7.5 μM 39 8 254 37 15571 602_3 7.5 μM 41 10 266 23 15571 602_4 7.5 μM 42 8 256 40 15571 40_2 7.5 μM 58 0 325 4 15571 40_3 7.5 μM 58 2 326 35 15571 40_4 7.5 μM 54 1 306 3 15571 40_5 7.5 μM 44 2 322 4 15571 40_6 7.5 μM 43 4 293 17 15571 40_7 7.5 μM 53 7 343 20 15571 40_8 7.5 μM 52 1 337 17 15572 604_1 7.5 μM 58 1 289 3 15572 604_2 7.5 μM 63 12 230 5 15572 604_3 7.5 μM 57 3 306 23 15572 604_4 7.5 μM 46 6 324 4 15572 603_1 7.5 μM 60 7 339 31 15572 603_2 7.5 μM 70 0 279 19 15572 603_3 7.5 μM 59 9 290 48 15572 603_4 7.5 μM 85 11 123 24 15573 605_1 7.5 μM 56 5 288 3 15573 605_2 7.5 μM 58 4 286 6 15573 605_3 7.5 μM 59 3 261 9 15573 605_4 7.5 μM 69 24 328 17 15573 606_1 7.5 μM 50 4 282 19 15573 606_2 7.5 μM 112 NA 133 NA 15573 606_3 7.5 μM 55 22 254 43 15573 606_4 7.5 μM 107 59 116 2 15574 607_1 7.5 μM 56 2 337 31 15574 607_2 7.5 μM 59 1 254 10 15574 607_3 7.5 μM 53 0 295 26 15574 607_4 7.5 μM 48 3 268 15 25248 608_1 7.5 μM 86 7 189 5 25248 608_2 7.5 μM 102 13 136 3 25248 608_3 7.5 μM 54 17 280 12 25248 608_4 7.5 μM 71 8 219 31 25248 608_5 7.5 μM 59 20 179 16 25248 608_6 7.5 μM 71 2 198 0 25248 608_7 7.5 μM 47 3 230 21 25248 608_8 7.5 μM 55 12 287 13 25248 608_9 7.5 μM 66 19 297 18 25249 609_1 7.5 μM 58 19 264 7 25249 609_2 7.5 μM 88 6 156 5 25249 609_3 7.5 μM 76 19 140 13 25249 609_4 7.5 μM 50 15 185 6 25249 609_5 7.5 μM 95 29 139 1 25249 609_6 7.5 μM 86 15 126 7 25249 609_7 7.5 μM 72 9 174 1 25249 609_8 7.5 μM 64 3 189 18 25249 609_9 7.5 μM 77 12 223 35 25250 610_1 7.5 μM 55 17 233 7 25250 610_2 7.5 μM 52 15 233 9 25250 610_3 7.5 μM 77 5 151 11 25250 610_4 7.5 μM 48 0 242 21 25250 610_5 7.5 μM 59 8 234 0 25250 610_6 7.5 μM 59 12 208 23 25250 610_7 7.5 μM 69 7 216 5 25250 610_8 7.5 μM 70 16 211 2 25250 610_9 7.5 μM 77 22 157 19 25251 611_1 7.5 μM 43 4 306 10 25251 611_2 7.5 μM 43 1 300 36 25251 611_3 7.5 μM 43 17 306 6 25251 611_4 7.5 μM 40 1 320 37 25251 611_5 7.5 μM 48 9 273 7 25251 611_6 7.5 μM 51 2 302 26 25251 611_7 7.5 μM 40 8 326 8 25251 611_8 7.5 μM 55 10 330 17 25251 611_9 7.5 μM 40 3 297 11 25252 612_1 7.5 μM 58 9 219 5 25252 612_2 7.5 μM 54 9 282 4 25252 612_3 7.5 μM 56 13 265 35 25252 612_4 7.5 μM 81 16 239 51 25252 612_5 7.5 μM 57 2 234 25 25252 612_6 7.5 μM 76 18 221 8 25252 612_7 7.5 μM 45 7 285 11 25252 612_8 7.5 μM 50 8 231 4 25252 612_9 7.5 μM 51 3 305 17 29636 271_1 7.5 μM 35 4 345 29 29636 271_1 7.5 μM 32 6 383 31 29636 271_1 7.5 μM 42 7 292 13 29636 271_1 7.5 μM 40 1 309 41 29636 271_1 7.5 μM 41 10 339 17 29636 271_1 7.5 μM 35 8 306 40 29636 271_1 7.5 μM 33 1 320 12 29636 271_1 7.5 μM 43 1 347 7 29636 271_1 7.5 μM 36 2 339 19 29636 271_1 7.5 μM 36 1 315 5 29636 271_1 7.5 μM 41 1 326 16 29636 271_1 7.5 μM 38 2 344 1 29636 271_1 7.5 μM 34 6 341 8 29636 271_1 7.5 μM 42 9 320 1 29636 271_1 7.5 μM 31 8 344 37 29636 271_1 7.5 μM 44 2 335 11 29636 271_1 7.5 μM 32 0 316 17 29636 271_1 7.5 μM 43 11 323 2 29636 271_1 7.5 μM 35 7 340 2 29636 271_1 7.5 μM 43 1 340 8 29636 271_1 7.5 μM 33 4 296 27 29636 271_1 7.5 μM 38 5 334 4 29636 271_1 7.5 μM 36 4 341 22 29636 271_1 7.5 μM 48 4 334 3 29636 271_1 7.5 μM 36 8 303 13 29636 271_1 7.5 μM 36 0 343 7 29636 271_1 7.5 μM 39 1 326 1 29636 271_1 7.5 μM 38 2 346 14 29636 271_1 7.5 μM 32 0 332 11 29636 271_1 7.5 μM 39 4 330 23 29636 271_1 7.5 μM 39 7 346 33 29636 271_1 7.5 μM 40 1 329 14 29636 271_1 7.5 μM 34 6 316 38 29636 271_1 7.5 μM 33 4 317 14 29636 271_1 7.5 μM 41 6 328 11 29636 271_1 7.5 μM 45 2 345 3 29636 271_1 7.5 μM 37 1 330 3 29636 271_1 7.5 μM 45 7 322 18 29636 271_1 7.5 μM 36 3 334 13 29636 271_1 7.5 μM 33 8 333 3 29636 271_1 7.5 μM 35 10 321 43 29636 271_1 7.5 μM 41 3 323 18 29636 271_1 7.5 μM 39 8 354 39 29636 271_1 7.5 μM 35 2 327 23 30599 613_1 7.5 μM 73 29 172 22 30599 613_2 7.5 μM 87 40 114 9 30599 613_3 7.5 μM 59 23 168 23 30599 613_4 7.5 μM 43 15 281 31 30599 613_5 7.5 μM 51 3 271 28 30600 614_1 7.5 μM 56 11 179 22 30600 614_2 7.5 μM 96 40 100 7 30600 614_3 7.5 μM 41 7 246 27 30600 614_4 7.5 μM 47 19 283 14 30600 614_5 7.5 μM 52 21 209 16 30600 615_1 7.5 μM 61 19 197 12 30600 615_2 7.5 μM 45 11 287 25 30600 615_3 7.5 μM 102 NA 115 NA 30600 615_4 7.5 μM 72 NA 170 NA 30600 615_5 7.5 μM 95 NA 138 NA 30601 285_2 7.5 μM 83 NA 165 NA 30601 285_3 7.5 μM 124 NA 111 NA 30601 285_4 7.5 μM 69 NA 183 NA 30601 285_5 7.5 μM 47 23 211 7 30601 285_6 7.5 μM 46 12 183 6 30601 617_1 7.5 μM 67 26 190 19 30601 617_2 7.5 μM 74 35 137 6 30601 617_3 7.5 μM 51 16 211 4 30601 617_4 7.5 μM 65 22 142 11 30601 617_5 7.5 μM 43 8 298 26 30601 616_1 7.5 μM 50 22 181 12 30601 616_2 7.5 μM 37 13 276 33 30601 616_3 7.5 μM 38 16 264 9 30601 616_4 7.5 μM 43 NA 304 NA 30601 616_5 7.5 μM 50 NA 229 NA 30602 619_1 7.5 μM 90 43 131 22 30602 619_2 7.5 μM 78 40 138 2 30602 619_3 7.5 μM 66 22 123 8 30602 619_4 7.5 μM 100 43 96 5 30602 619_5 7.5 μM 75 17 157 5 30602 618_1 7.5 μM 46 1 226 12 30602 618_2 7.5 μM 68 NA 151 NA 30602 618_3 7.5 μM 52 4 207 18 30602 618_4 7.5 μM 57 12 223 2 30602 618_5 7.5 μM 54 2 211 3 30603 620_1 7.5 μM 106 23 110 16 30603 620_2 7.5 μM 48 10 243 18 30603 620_3 7.5 μM 53 1 174 32 30603 620_4 7.5 μM 81 0 138 15 30603 620_5 7.5 μM 56 5 218 9 30604 621_1 7.5 μM 39 4 304 10 30604 621_2 7.5 μM 35 7 311 3 30604 621_3 7.5 μM 67 18 142 8 30604 621_4 7.5 μM 34 6 273 21 30604 621_5 7.5 μM 36 5 266 18 30605 622_1 7.5 μM 42 1 242 28 30605 622_2 7.5 μM 31 10 300 8 30605 622_3 7.5 μM 35 3 319 11 30605 622_4 7.5 μM 37 4 281 5 30605 622_5 7.5 μM 39 5 306 11 30606 623_1 7.5 μM 47 3 287 1 30606 623_2 7.5 μM 74 23 166 7 30606 623_3 7.5 μM 82 1 149 8 30606 623_4 7.5 μM 66 9 135 8 30606 623_5 7.5 μM 78 7 128 12 30608 624_1 7.5 μM 84 13 185 25 30608 624_2 7.5 μM 35 2 245 9 30608 624_3 7.5 μM 31 3 267 9 30608 624_4 7.5 μM 39 16 257 13 30608 624_5 7.5 μM 34 3 283 4 30666 625_1 7.5 μM 45 5 286 39 30666 625_2 7.5 μM 39 3 280 13 30666 625_3 7.5 μM 40 10 258 9 30666 625_4 7.5 μM 41 14 234 39 30666 625_5 7.5 μM 42 5 293 26 30666 625_6 7.5 μM 44 0 284 25 30666 625_7 7.5 μM 46 3 271 4 30666 625_8 7.5 μM 47 5 256 17 30666 625_9 7.5 μM 40 7 302 2 30667 626_1 7.5 μM 38 1 279 10 30667 626_2 7.5 μM 39 21 329 22 30667 626_3 7.5 μM 59 12 265 65 30667 626_4 7.5 μM 39 5 318 25 30667 626_5 7.5 μM 36 2 302 33 30667 626_6 7.5 μM 36 6 273 34 30667 626_7 7.5 μM 30 0 299 29 30667 626_8 7.5 μM 35 4 277 43 30667 626_9 7.5 μM 32 3 275 22 30668 627_1 7.5 μM 71 3 131 11 30668 627_2 7.5 μM 49 4 226 30 30668 627_3 7.5 μM 64 5 147 8 30668 627_4 7.5 μM 52 6 176 9 30668 627_5 7.5 μM 78 14 108 3 30668 627_6 7.5 μM 40 1 183 23 30668 627_7 7.5 μM 85 8 116 2 30668 627_8 7.5 μM 45 1 128 7 30668 627_9 7.5 μM 42 5 215 36 30669 628_1 7.5 μM 90 11 120 15 30669 628_2 7.5 μM 73 12 124 4 30669 628_3 7.5 μM 88 2 115 4 30669 628_4 7.5 μM 54 4 190 18 30669 628_5 7.5 μM 64 1 138 3 30669 628_6 7.5 μM 62 4 138 11 30669 628_7 7.5 μM 55 1 138 13 30669 628_8 7.5 μM 62 1 140 5 30669 628_9 7.5 μM 79 10 134 22 30711 629_1 7.5 μM 42 1 252 47 30711 629_2 7.5 μM 40 2 295 30 30711 629_3 7.5 μM 46 1 302 78 30711 629_4 7.5 μM 41 3 260 16 30711 629_5 7.5 μM 41 1 284 3 30711 629_6 7.5 μM 43 0 262 1 30711 629_7 7.5 μM 43 3 278 65 30711 629_8 7.5 μM 53 5 234 24 30711 629_9 7.5 μM 37 4 289 1 30711 629_10 7.5 μM 47 6 292 6 30711 629_11 7.5 μM 50 5 224 20 30712 630_1 7.5 μM 44 2 282 22 30712 630_2 7.5 μM 45 6 297 23 30712 630_3 7.5 μM 46 2 272 10 30713 631_1 7.5 μM 45 2 294 10 30713 631_2 7.5 μM 42 0 285 14 30713 631_3 7.5 μM 38 3 319 21 30713 631_4 7.5 μM 43 3 282 4 30713 631_5 7.5 μM 54 2 173 17 30713 631_6 7.5 μM 37 0 315 10 30713 631_7 7.5 μM 40 4 317 2 30713 631_8 7.5 μM 44 1 275 5 30713 631_9 7.5 μM 47 2 233 8 30713 631_10 7.5 μM 108 18 101 3 30714 632_1 7.5 μM 48 4 210 4 30714 632_2 7.5 μM 53 5 256 5 30714 632_3 7.5 μM 60 5 224 19 30714 632_4 7.5 μM 89 12 117 11 30714 632_5 7.5 μM 39 6 312 6 30714 632_6 7.5 μM 40 2 278 31 30714 632_7 7.5 μM 86 1 160 21 30714 632_8 7.5 μM 57 17 278 40 30714 632_9 7.5 μM 51 7 236 13 30715 304_2 7.5 μM 53 5 206 18 30715 304_3 7.5 μM 70 11 142 24 30715 304_4 7.5 μM 88 1 120 10 30715 304_5 7.5 μM 82 15 123 7 30715 304_6 7.5 μM 43 4 264 12 30715 304_7 7.5 μM 41 5 266 49 30715 304_8 7.5 μM 43 1 291 12 30715 304_9 7.5 μM 36 3 285 18 30715 304_10 7.5 μM 42 1 280 40 33376 633_1 7.5 μM 53 1 234 50 33376 633_2 7.5 μM 45 5 301 7 33376 633_3 7.5 μM 53 7 263 17 33376 633_4 7.5 μM 53 4 229 22 33376 633_5 7.5 μM 43 3 264 36 33376 633_6 7.5 μM 53 5 247 12 33376 633_7 7.5 μM 49 6 289 6 33376 633_8 7.5 μM 64 1 238 24 33376 633_9 7.5 μM 63 2 249 28 33377 634_1 7.5 μM 57 9 250 14 33377 634_2 7.5 μM 53 10 265 3 33377 634_3 7.5 μM 48 2 275 10 33377 634_4 7.5 μM 39 6 287 12 33377 634_5 7.5 μM 49 1 255 22 33377 634_6 7.5 μM 51 2 291 15 33377 634_7 7.5 μM 47 5 297 16 33377 634_8 7.5 μM 42 9 311 14 33377 634_9 7.5 μM 47 5 271 23 33378 635_1 7.5 μM 56 11 257 3 33378 635_2 7.5 μM 56 5 213 23 33378 635_3 7.5 μM 61 8 215 8 33378 635_4 7.5 μM 58 15 232 16 33378 635_5 7.5 μM 48 3 316 20 33378 635_6 7.5 μM 59 5 262 30 33378 635_7 7.5 μM 55 7 287 15 33378 635_8 7.5 μM 42 1 284 3 33378 635_9 7.5 μM 40 0 277 23 33379 636_1 7.5 μM 50 2 239 7 33379 636_2 7.5 μM 74 16 204 10 33379 636_3 7.5 μM 55 4 201 3 33379 636_4 7.5 μM 54 2 238 7 33379 636_5 7.5 μM 52 5 207 43 33379 636_6 7.5 μM 47 3 249 6 33379 636_7 7.5 μM 48 5 241 1 33379 636_8 7.5 μM 37 7 304 12 33379 636_9 7.5 μM 62 9 245 5 33380 637_1 7.5 μM 39 1 219 25 33380 637_2 7.5 μM 59 1 197 11 33380 637_3 7.5 μM 56 1 250 19 33380 637_4 7.5 μM 53 7 244 36 33380 637_5 7.5 μM 73 13 297 34 33380 637_6 7.5 μM 65 1 124 17 33380 637_7 7.5 μM 74 5 133 5 33380 637_8 7.5 μM 53 2 207 7 33380 637_9 7.5 μM 54 15 226 26 39806 638_1 7.5 μM 37 7 283 31 39806 638_2 7.5 μM 49 11 291 30 39806 638_3 7.5 μM 41 1 270 20 39806 638_4 7.5 μM 42 13 267 9 39806 638_5 7.5 μM 50 1 184 5 39806 638_6 7.5 μM 38 1 276 15 39806 638_7 7.5 μM 56 1 292 4 39806 638_8 7.5 μM 41 4 267 11 39806 638_9 7.5 μM 41 4 218 33 39807 639_1 7.5 μM 48 15 293 30 39807 639_2 7.5 μM 38 3 269 2 39807 639_3 7.5 μM 72 5 167 3 39807 639_4 7.5 μM 69 38 242 36 39807 639_5 7.5 μM 47 6 303 36 39807 639_6 7.5 μM 53 6 179 5 39807 639_7 7.5 μM 51 3 189 8 39807 639_8 7.5 μM 42 3 185 19 39807 639_9 7.5 μM 45 3 202 15 39808 640_1 7.5 μM 39 5 265 7 39808 640_2 7.5 μM 37 4 272 56 39808 640_3 7.5 μM 38 3 260 17 39808 640_4 7.5 μM 33 4 255 2 39808 640_5 7.5 μM 38 3 253 3 39808 640_6 7.5 μM 40 8 216 10 39808 640_7 7.5 μM 39 8 310 7 39808 640_8 7.5 μM 41 6 282 21 39808 640_9 7.5 μM 40 5 269 12 44439 641_1 7.5 μM 35 6 336 32 44439 641_2 7.5 μM 67 20 161 6 44439 641_3 7.5 μM 34 9 317 30 44439 641_4 7.5 μM 62 18 193 9 44439 641_5 7.5 μM 34 4 280 3 44439 641_6 7.5 μM 43 1 315 45 44439 641_7 7.5 μM 45 17 307 53 44439 641_8 7.5 μM 41 0 294 41 44439 641_9 7.5 μM 37 2 334 43 44440 361_2 7.5 μM 36 1 303 15 44440 361_3 7.5 μM 32 3 315 12 44440 361_4 7.5 μM 41 1 299 7 44440 361_5 7.5 μM 40 5 295 6 44440 361_6 7.5 μM 40 2 296 30 44440 361_7 7.5 μM 39 1 300 55 44440 361_8 7.5 μM 45 6 285 45 44440 361_9 7.5 μM 44 6 321 26 44440 361_10 7.5 μM 46 7 290 18 44441 362_2 7.5 μM 50 4 277 4 44441 362_3 7.5 μM 40 6 296 8 44441 362_4 7.5 μM 37 5 340 18 44441 362_5 7.5 μM 45 2 266 21 44441 362_6 7.5 μM 39 7 263 0 44441 362_7 7.5 μM 41 12 262 36 44441 362_8 7.5 μM 35 13 313 6 44441 362_9 7.5 μM 36 8 300 20 44441 362_10 7.5 μM 48 10 293 1 46391 642_1 7.5 μM 51 25 278 6 46391 642_2 7.5 μM 46 2 303 4 46391 642_3 7.5 μM 48 3 297 11 46391 642_4 7.5 μM 45 11 320 37 46391 642_5 7.5 μM 71 32 303 40 46391 642_6 7.5 μM 47 15 298 16 46391 642_7 7.5 μM 38 6 277 5 46391 642_8 7.5 μM 38 3 280 20 46391 642_9 7.5 μM 51 20 285 16 46391 642_10 7.5 μM 32 7 293 20 46391 642_11 7.5 μM 42 2 291 2 46391 642_12 7.5 μM 40 3 317 19 46391 642_13 7.5 μM 39 11 295 5 46391 642_14 7.5 μM 52 20 295 16 46391 642_15 7.5 μM 39 8 316 38 46391 642_16 7.5 μM 35 2 294 30 46391 642_17 7.5 μM 51 5 292 8 46391 643_1 7.5 μM 39 4 276 16 46392 644_1 7.5 μM 39 0 321 7 46392 644_2 7.5 μM 46 4 308 4 46392 644_3 7.5 μM 44 1 317 3 46392 644_4 7.5 μM 38 6 315 11 46392 645_1 7.5 μM 46 5 342 42 46392 645_2 7.5 μM 37 5 292 25 46392 645_3 7.5 μM 46 16 317 30 46392 645_4 7.5 μM 47 8 381 102 46392 645_5 7.5 μM 42 2 269 4 46393 646_1 7.5 μM 49 4 295 2 46393 646_2 7.5 μM 49 9 304 38 46393 646_3 7.5 μM 44 6 298 50 46393 646_4 7.5 μM 43 1 296 41 46393 646_5 7.5 μM 35 1 260 3 46393 646_6 7.5 μM 40 2 281 67 46393 646_7 7.5 μM 38 1 278 44 46393 646_8 7.5 μM 42 6 262 49 46393 646_9 7.5 μM 38 3 289 24 46393 646_10 7.5 μM 38 1 317 4 46393 646_11 7.5 μM 42 1 320 34 46393 646_12 7.5 μM 36 5 323 8 46393 646_13 7.5 μM 41 3 262 27 46393 646_14 7.5 μM 46 13 315 18 46393 646_15 7.5 μM 42 4 340 27 46393 646_16 7.5 μM 45 8 360 14 46393 646_17 7.5 μM 44 1 303 3 46393 646_18 7.5 μM 50 2 304 28 46393 646_19 7.5 μM 54 10 217 25 51241 425_2 7.5 μM 49 12 296 3 51241 425_3 7.5 μM 48 6 297 10 51241 425_4 7.5 μM 52 5 275 25 51241 425_5 7.5 μM 40 6 284 29 51241 425_6 7.5 μM 39 5 301 22 51241 425_7 7.5 μM 39 4 263 13 51241 425_8 7.5 μM 32 5 188 13 51241 425_9 7.5 μM 42 5 286 2 51241 425_10 7.5 μM 34 3 165 17

Example 6—Activity of Exon-Exon Spanning Oligonucleotides

Oligonucleotides designed to be complemnentary across exon-exon junctions of SNHG14-023 (ENST00000554726) were tested for their ability to reduce the SNHG14 transcript in the region downstream of SNORD109B (also termed UBE3A suppressor or UBE3A-SUP in the data table). Furthermore, the ability to induce UBE3A mRNA re-expression was analyzed. The oligonucleotides primarily span exon2 and exon3 (i.e. are complementary to a region in exon2 and a region in exon 3).

The oligonucleotides were screened according to the protocol for screening oligonucleotides in human neuronal cell cultures described in the section Example 5.

The results are shown in table 9.

TABLE 9 Oligonucleotide activity in patient derived human neuronal cell cultures. CMP ID Conc % of Mock % of Mock NO μM UBE3A-SUP sd UBE3A sd 674_1 7.5 μM 47 2 214 12 675_1 7.5 μM 44 6 265 10 676_1 7.5 μM 44 3 284 16 677_1 7.5 μM 55 19 351 18 678_1 7.5 μM 41 11 257 1 656_1 7.5 μM 46 3 140 19 657_1 7.5 μM 35 7 218 27 658_1 7.5 μM 38 12 253 43 659_1 7.5 μM 39 7 274 6 660_1 7.5 μM 38 8 275 29 661_1 7.5 μM 43 13 246 21 662_1 7.5 μM 27 10 290 5 663_1 7.5 μM 28 0 287 23 664_1 7.5 μM 27 2 288 14 665_1 7.5 μM 37 9 321 47 666_1 7.5 μM 54 1 259 10 667_1 7.5 μM 47 8 236 2 647_1 7.5 μM 19 3 300 25 648_1 7.5 μM 22 7 320 3 649_1 7.5 μM 34 8 326 2 650_1 7.5 μM 44 4 292 7 651_1 7.5 μM 36 5 254 9 652_1 7.5 μM 21 2 314 18 653_1 7.5 μM 24 5 299 41 654_1 7.5 μM 31 2 344 41 655_1 7.5 μM 60 9 301 3 668_1 7.5 μM 21 3 297 11 669_1 7.5 μM 24 5 296 27 670_1 7.5 μM 30 3 274 55 671_1 7.5 μM 27 6 263 35 672_1 7.5 μM 27 6 280 50 673_1 7.5 μM 33 2 290 19

Example 7—Testing in vitro efficacy and potency of selected oligonucleotides

Based on the screenings in examples 2 to 5 above 52 oligonucleotides were selected for potency and efficacy testing.

The oligonucleotides were screened in human AS patient derived cells as described in the Materials and Method section “Screening oligonucleotides in human neuronal cell cultures—96 well system” with the following modifications:

For UBE3a-Sense primer commercially available primers and probe from ThermoFisher: Hs00166580_m1 amplifying a 94 bp sequence in position 838 of refseq ID NM_000462.3 were used.

Each plate include PBS controls (instead on a non-targeting oligonucleotide) and the positive control oligonucleotides CMP ID NO: 186_1 and 39_1 identified in previous screens were included. The additional control oligonucleotides described in the materials and method section were not included. Oligonucleotide test concentrations were from 31.6 μM to 1 nM using a 10 point half-log dilution. All oligonucleotides were tested in 5 independent experiments in 5 different weeks. In the data QC process some plates were removed from the analysis if these were obvious outliers e.g. no PCR product detected. After this filtration there is a minimum of three independent experiments behind each the reported values.

The EC50 (UBE3A mRNA re-expression) and IC50 (reduction of the SNHG14 transcript in the region downstream of SNORD109B, also termed UBE3A suppressor or UBE3A-SUP in the data table) were determined after curve fitting using a 4 parameter sigmoidal dose-response model. Fitting was executed using the fit engine available inside the Biobook software by IDBS (XLfit). From the curve-fitting the maximum obtainable up-regulation of UBE3A (UBE3A Max Up) and the maximum obtainable knockdown of UBE3A-SUP (UB3E3A-SUP max Kd) were determined. Both are shown as % of control (PBS treated cells). The results are shown in table 10, values are reported as geometric means of each biological replicate.

TABLE 10 Oligonucleotide EC50 and IC 50 values and maximum UBE3A upregulation and UBE3A suppressor knock down. IC50 UBE3A- CMP EC50 ↓ UBE3A SUP ID ↑ UBE3A- Max max NO UBE3A Sd SUP Sd Kd Sd Kd Sd 586_9 0.02 0.02 0.01 0.00 329.4 25.5 33.5 3.8 585_1 0.03 0.01 0.03 0.02 301.6 18.3 31.0 5.3 572_7 0.03 0.00 0.01 0.03 294.1 30.4 31.3 3.5 591_1 0.03 0.02 0.01 0.00 387.3 46.0 41.4 2.8 585_8 0.04 0.02 0.02 0.01 312.3 23.1 35.2 3.3 626_7 0.04 0.02 0.02 0.00 362.5 44.6 38.7 3.3 621_2 0.04 0.03 0.02 0.01 264.5 19.6 24.7 3.9 624_3 0.04 0.03 0.04 0.03 288.1 19.2 29.7 5.2 169_52 0.04 0.04 0.02 0.01 303.4 23.1 27.3 1.8 624_5 0.04 0.07 0.01 0.01 249.2 16.3 16.4 1.4 586_5 0.04 0.01 0.01 0.00 364.4 43.9 30.4 3.3 626_8 0.04 0.03 0.01 0.01 338.7 24.0 39.1 2.6 169_50 0.05 0.02 0.02 0.02 280.3 23.0 28.3 2.4 572_6 0.05 0.01 0.01 0.02 298.5 22.4 36.3 4.0 639_5 0.05 0.03 0.01 0.00 327.7 22.0 38.2 3.6 592_2 0.05 0.03 0.02 0.05 364.9 27.1 36.4 3.6 586_8 0.05 0.03 0.02 0.01 366.6 35.1 38.0 3.9 625_6 0.06 0.03 0.01 0.00 335.5 34.7 32.5 1.9 644_3 0.06 0.04 0.01 0.02 298.5 22.0 25.3 1.6 586_4 0.06 0.03 0.01 0.01 354.3 31.5 33.0 2.3 642_12 0.06 0.05 0.02 0.01 289.2 14.8 24.7 3.0 572_5 0.07 0.09 0.02 0.00 312.7 25.9 31.5 3.0 592_4 0.07 0.06 0.03 0.01 341.1 31.9 35.7 1.8 622_3 0.07 0.04 0.02 0.01 300.9 21.0 27.6 3.6 622_5 0.07 0.01 0.02 0.01 306.2 13.5 24.4 4.0 616_4 0.07 0.04 0.03 0.02 293.8 17.9 29.1 5.0 304_6 0.08 0.08 0.02 0.00 318.1 39.2 43.8 3.9 638_8 0.08 0.01 0.01 0.01 354.8 30.6 42.4 4.1 622_4 0.08 0.07 0.02 0.01 330.3 24.8 29.5 2.4 642_13 0.08 0.07 0.04 0.03 268.4 21.0 26.8 2.5 573_8 0.08 0.01 0.04 0.02 320.1 34.4 34.3 3.4 241_9 0.09 0.04 0.04 0.03 352.6 26.4 34.1 2.3 304_10 0.09 0.07 0.03 0.01 289.5 19.9 28.3 2.8 636_8 0.10 0.08 0.03 0.04 330.8 34.1 53.9 13.4 598_4 0.11 0.06 0.03 0.04 295.0 15.1 41.3 2.2 586_6 0.11 0.10 0.02 0.02 316.2 21.2 23.8 3.5 621_1 0.11 0.21 0.02 0.01 311.9 19.2 27.5 5.2 331_1 0.12 0.02 0.03 0.02 293.6 49.0 25.1 5.4 626_9 0.13 0.12 0.02 0.03 302.2 32.6 34.4 2.2 169_56 0.14 0.18 0.02 0.01 356.5 22.3 26.8 2.2 631_6 0.14 0.30 0.04 0.00 292.9 25.1 33.5 4.9 186_1 0.16 0.02 0.04 0.05 371.7 70.1 32.5 5.5 611_7 0.16 0.15 0.02 0.01 369.2 29.3 37.2 3.9 165_1 0.17 0.02 0.07 0.12 266.3 NA 26.7 NA 646_16 0.18 0.15 0.03 0.02 306.0 9.0 30.6 2.9 640_4 0.20 0.10 0.02 0.01 328.4 31.0 40.4 7.0 631_1 0.22 0.07 0.07 0.02 324.6 1.6 47.5 8.1 590_13 0.23 0.59 0.02 0.02 353.4 22.3 31.8 2.2 172_1 0.24 0.10 0.11 0.14 254.2 NA 34.2 NA 35_2 0.26 0.02 0.06 0.09 257.9 NA 22.3 NA 425_5 0.26 0.14 0.08 0.08 317.3 33.9 32.9 2.4 359_1 0.27 0.03 0.03 0.08 260.5 NA 31.3 NA 209_1 0.28 0.08 0.03 0.03 339.9 30.6 48.2 11.6 123_1 0.28 0.13 0.26 0.08 235.9 NA 51.8 NA 361_1 0.29 0.10 0.06 0.02 331.9 17.2 30.7 6.3 602_1 0.31 0.33 0.15 0.20 340.3 21.7 42.2 5.0 NA 0.44 0.12 0.15 0.18 251.3 NA 24.6 NA 287_1 0.45 0.09 0.04 0.02 318.1 45.2 28.8 9.3 303_1 0.46 0.05 0.09 0.15 259.9 NA 30.9 NA 379_1 0.47 0.02 0.08 0.16 247.2 NA 22.5 NA 405_1 0.48 0.42 0.04 0.01 323.0 56.2 32.5 11.9 39_1 0.51 0.20 0.06 0.06 341.2 30.3 40.4 4.7 206_1 0.52 0.07 0.14 0.31 262.9 NA 30.5 NA 155_1 0.53 0.10 NA 0.53 260.8 NA 26.7 NA 362_1 0.57 0.25 0.09 0.02 328.1 57.3 27.4 8.6 178_1 0.58 0.35 0.11 0.04 334.3 50.8 26.6 8.0 48_1 0.59 0.02 0.07 0.56 262.7 NA 27.2 NA 200_1 0.62 0.51 0.15 0.06 331.0 54.3 33.1 6.2 361_5 0.67 0.18 0.07 0.00 307.1 22.9 32.1 4.5 597_4 0.67 0.51 0.10 0.06 325.3 17.3 35.3 2.7 85_1 0.68 0.06 0.28 0.41 255.5 NA 35.1 NA 278_1 0.69 0.67 0.08 0.09 313.8 33.4 27.2 4.6 271_1 0.69 0.00 0.03 0.65 247.3 NA 24.0 NA 403_1 0.77 0.57 0.11 0.09 296.4 55.0 28.8 7.0 204_1 0.78 0.59 0.05 0.05 316.1 35.5 36.3 7.9 116_1 0.91 0.05 0.09 0.43 240.6 NA 31.6 NA 124_1 0.92 0.29 0.55 0.94 190.0 NA 43.9 NA 237_8 0.93 0.66 0.05 0.03 376.2 32.8 33.6 3.7 378_1 0.95 0.64 0.13 0.09 317.7 30.1 48.5 6.1 126_2 0.95 0.05 0.12 0.70 219.7 NA 45.0 NA 373_1 1.03 0.63 0.13 0.08 321.7 38.6 27.5 4.8 641_5 1.16 1.36 0.07 0.06 335.1 28.9 26.6 5.1 207_1 1.18 0.58 0.18 0.06 318.5 42.9 44.0 7.2 19_1 1.50 0.19 0.24 1.07 261.7 NA 28.4 NA 175_1 1.51 0.42 0.17 0.11 333.5 23.8 29.2 5.2 304_1 1.55 0.09 0.08 0.11 297.8 26.2 32.5 5.7 399_1 1.86 2.50 0.44 0.26 340.1 52.2 39.6 4.3 38_1 2.12 0.10 0.34 0.43 257.3 NA 45.1 NA 222_1 2.29 0.75 0.28 0.12 298.2 34.9 26.8 5.6 187_1 2.30 1.39 1.00 0.91 315.3 38.4 28.6 6.2 272_1 2.32 1.39 0.24 0.16 330.4 41.2 37.1 6.1 18_1 2.42 0.21 0.24 2.00 271.0 NA 29.3 NA 118_1 2.78 0.30 0.31 0.07 205.4 NA 40.4 NA 35_1 2.93 4.94 3.61 1.52 258.4 NA 48.2 NA 233_1 3.14 1.68 0.35 0.16 330.3 20.1 29.3 5.2 220_1 3.47 0.99 1.02 0.48 315.5 27.4 29.6 7.6 33_1 3.97 0.41 1.07 NA 265.7 NA 32.2 NA 109_1 4.06 1.45 1.33 0.67 231.7 44.7 39.6 3.9 40_1 4.17 0.05 0.12 3.74 263.6 NA 38.3 NA 115_1 4.98 0.15 0.25 NA 184.2 NA 47.0 NA 161_1 6.55 3.20 1.25 1.24 294.0 24.8 32.1 7.4 105_4 6.61 1.62 1.38 4.20 NA NA 50.6 NA 19_2 6.66 1.17 3.17 1.52 201.7 NA 57.7 NA 104_1 7.75 6.77 1.67 1.05 267.9 25.5 42.5 4.1 18_2 20.00 1.67 3.50 NA 245.9 NA 46.4 NA 108_1 20.00 0.61 1.27 NA 219.6 NA 51.2 NA 129_2 20.00 0.08 1.10 NA 165.8 NA 56.5 NA 141_1 20.00 0.03 0.15 NA 159.0 NA 64.1 NA 142_1 20.00 1.04 1.12 NA 133.1 NA 57.6 NA 145_1 20.00 1.30 1.81 NA 139.0 NA 56.9 NA

Claims

1. An antisense oligonucleotide for inducing human paternal ubiquitin-protein ligase E3A (UBE3A) expression, wherein the antisense oligonucleotide comprises a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 98% complementarity to position 25278410 to 25419462 on human chromosome 15, wherein the oligonucleotide comprises one or more modified nucleosides.

2. The oligonucleotide of claim 1, wherein the contiguous nucleotide sequence is complementary to a region of a target nucleic acid of SEQ ID NO: 1 and/or 2.

3. The oligonucleotide of claim 1, wherein the contiguous nucleotide sequence is 100% complementary to a region of a target nucleic acid of position 1 to 55318 of SEQ ID NO: 1.

4. The oligonucleotide of claim 2, wherein the contiguous nucleotide sequence is complementary to a sub-sequence of SEQ ID NO: 1, the sub-sequence is selected from the group consisting of positions 10 to 75, 77 to 91, 93 to 108, 168 to 213, 217 to 282, 284 to 299, 301 to 328, 330 to 344, 361 to 400, 415 to 447, 449 to 470, 472 to 487, 489 to 521, 523 to 540, 551 to 570, 590 to 638, 652 to 670, 672 to 733, 735 to 756, 758 to 773, 781 to 829, 831 to 870, 882 to 903, 918 to 949, 961 to 990, 1007 to 1021, 1019 to 1050, 1052 to 1090, 1092 to 1139, 1147 to 1179, 1175 to 1212, 1220 to 1242, 1245 to 1259, 1265 to 1278, 1285 to 1323, 1317 to 1330, 1337 to 1355, 1357 to 1403, 1405 to 1421, 1423 to 1481, 1486 to 1515, 1521 to 1581, 1611 to 1633, 1631 to 1644, 1635 to 1663, 1669 to 1684, 1685 to 1709, 1711 to 1724, 1726 to 1746, 1754 to 1808, 1819 to 1860, 1862 to 1878, 1896 to 1910, 1923 to 1944, 1946 to 1987, 1985 to 2051, 2053 to 2082, 2088 to 2104, 2106 to 2125, 2132 to 2207, 2209 to 2234, 2247 to 2261, 2263 to 2286, 2290 to 2306, 2308 to 2329, 2347 to 2391, 2398 to 2431, 2447 to 2468, 2470 to 2555, 2565 to 2579, 2579 to 2592, 2589 to 2605, 2594 to 2657, 2672 to 2687, 2692 to 2705, 2703 to 2721, 2770 to 2824, 2826 to 2841, 2838 to 2851, 2843 to 2889, 2896 to 2930, 2930 to 2967, 2965 to 2988, 2984 to 3028, 3024 to 3080, 3081 to 3135, 3140 to 3176, 3168 to 3189, 3197 to 3222, 3212 to 3226, 3221 to 3248, 3243 to 3256, 3250 to 3264, 3266 to 3292, 3326 to 3343, 3345 to 3391, 3400 to 3422, 3424 to 3441, 3434 to 3447, 3443 to 3503, 3495 to 3508, 3505 to 3558, 3589 to 3609, 3611 to 3641, 3662 to 3696, 3698 to 3719, 3723 to 3790, 3810 to 3854, 3858 to 3873, 3902 to 3968, 3971 to 4009, 4005 to 4018, 4011 to 4030, 4032 to 4077, 4082 to 4114, 4123 to 4140, 4150 to 4164, 4166 to 4183, 4185 to 4243, 4248 to 4268, 4284 to 4313, 4317 to 4348, 4364 to 4471, 4473 to 4491, 4494 to 4519, 4521 to 4535, 4545 to 4560, 4567 to 4606, 4616 to 4714, 4725 to 4755, 4757 to 4786, 4788 to 4852, 4856 to 4910, 4912 to 4935, 4937 to 4970, 4972 to 5010, 5058 to 5078, 5080 to 5116, 5110 to 5124, 5135 to 5166, 5168 to 5201, 5203 to 5247, 5261 to 5276, 5278 to 5293, 5314 to 5330, 5332 to 5382, 5398 to 5414, 5427 to 5456, 5458 to 5471, 5487 to 5500, 5506 to 5545, 5561 to 5577, 5580 to 5617, 5607 to 5620, 5619 to 5642, 5644 to 5683, 5685 to 5698, 5713 to 5759, 5756 to 5769, 5784 to 5803, 5801 to 5865, 5873 to 5905, 5907 to 5937, 5939 to 5985, 5987 to 6017, 6016 to 6039, 6028 to 6092, 6102 to 6127, 6127 to 6152, 6151 to 6171, 6178 to 6206, 6217 to 6234, 6224 to 6270, 6272 to 6289, 6291 to 6310, 6312 to 6357, 6367 to 6389, 6396 to 6422, 6440 to 6454, 6456 to 6482, 6484 to 6513, 6505 to 6519, 6518 to 6553, 6552 to 6565, 6557 to 6590, 6596 to 6628, 6640 to 6675, 6686 to 6711, 6714 to 6746, 6781 to 6818, 6832 to 6885, 6889 to 6912, 6920 to 6938, 6940 to 6960, 6954 to 6976, 6998 to 7033, 7035 to 7061, 7071 to 7143, 7159 to 7214, 7253 to 7266, 7268 to 7281, 7283 to 7328, 7329 to 7343, 7338 to 7355, 7345 to 7374, 7374 to 7387, 7383 to 7396, 7389 to 7405, 7399 to 7413, 7420 to 7437, 7427 to 7448, 7450 to 7503, 7495 to 7565, 7561 to 7616, 7618 to 7703, 7717 to 7772, 7776 to 7838, 7852 to 7869, 7882 to 7910, 7919 to 7942, 7944 to 7957, 7959 to 7977, 7979 to 7996, 7998 to 8014, 8030 to 8046, 8059 to 8092, 8100 to 8113, 8115 to 8141, 8143 to 8175, 8179 to 8192, 8187 to 8208, 8205 to 8219, 8210 to 8229, 8231 to 8252, 8254 to 8298, 8302 to 8316, 8306 to 8329, 8331 to 8357, 8400 to 8443, 8443 to 8456, 8445 to 8460, 8472 to 8505, 8494 to 8507, 8554 to 8569, 8571 to 8653, 8659 to 8673, 8675 to 8694, 8696 to 8713, 8736 to 8844, 8847 to 8909, 8915 to 8959, 8961 to 8975, 8993 to 9009, 9024 to 9048, 9050 to 9063, 9089 to 9120, 9127 to 9166, 9191 to 9249, 9257 to 9285, 9288 to 9302, 9331 to 9397, 9399 to 9438, 9437 to 9455, 9483 to 9505, 9507 to 9526, 9583 to 9598, 9600 to 9613, 9628 to 9641, 9653 to 9674, 9676 to 9690, 9745 to 9758, 9752 to 9780, 9796 to 9809, 9811 to 9825, 9832 to 9853, 9877 to 9899, 9901 to 9932, 10000 to 10016, 10029 to 10049, 10051 to 10071, 10089 to 10120, 10111 to 10127, 10122 to 10203, 10211 to 10237, 10239 to 10256, 10258 to 10285, 10287 to 10304, 10306 to 10350, 10352 to 10375, 10381 to 10402, 10412 to 10470, 10474 to 10488, 10508 to 10557, 10565 to 10630, 10632 to 10674, 10698 to 10711, 10701 to 10714, 10704 to 10718, 10720 to 10740, 10742 to 10785, 10786 to 10809, 10811 to 10829, 10832 to 10867, 10869 to 10930, 10932 to 10950, 10959 to 10996, 10998 to 11028, 11037 to 11077, 11079 to 11105, 11115 to 11132, 11134 to 11154, 11156 to 11196, 11206 to 11239, 11241 to 11255, 11266 to 11287, 11299 to 11329, 11331 to 11352, 11358 to 11403, 11405 to 11432, 11434 to 11480, 11482 to 11535, 11539 to 11573, 11584 to 11732, 11731 to 11763, 11765 to 11782, 11784 to 11813, 11815 to 11829, 11831 to 11852, 11854 to 11871, 11866 to 11895, 11930 to 11943, 11975 to 12007, 11996 to 12012, 12017 to 12040, 12050 to 12083, 12088 to 12111, 12133 to 12151, 12161 to 12174, 12179 to 12225, 12238 to 12256, 12265 to 12278, 12296 to 12360, 12362 to 12381, 12384 to 12399, 12400 to 12475, 12487 to 12502, 12504 to 12531, 12533 to 12562, 12564 to 12602, 12627 to 12646, 12655 to 12679, 12681 to 12698, 12700 to 12812, 12828 to 12876, 12877 to 12913, 12932 to 12945, 12936 to 12967, 12988 to 13002, 12996 to 13009, 13018 to 13035, 13031 to 13049, 13056 to 13093, 13096 to 13126, 13128 to 13142, 13144 to 13193, 13201 to 13221, 13223 to 13280, 13282 to 13298, 13300 to 13315, 13307 to 13320, 13315 to 13331, 13351 to 13411, 13422 to 13437, 13439 to 13456, 13461 to 13483, 13485 to 13541, 13543 to 13560, 13574 to 13606, 13618 to 13646, 13778 to 13801, 13994 to 14009, 14508 to 14521, 15049 to 15067, 15069 to 15090, 15102 to 15139, 15142 to 15180, 15182 to 15205, 15238 to 15252, 15254 to 15277, 15292 to 15320, 15322 to 15348, 15343 to 15358, 15362 to 15387, 15399 to 15414, 15416 to 15445, 15459 to 15528, 15537 to 15592, 15610 to 15638, 15640 to 15653, 15655 to 15717, 15719 to 15738, 15757 to 15778, 15783 to 15801, 15818 to 15838, 15835 to 15849, 15840 to 15857, 15856 to 15898, 15900 to 15916, 15931 to 15972, 15988 to 16028, 16030 to 16075, 16103 to 16164, 16207 to 16243, 16233 to 16246, 16255 to 16329, 16349 to 16376, 16378 to 16404, 16399 to 16419, 16421 to 16461, 16463 to 16479, 16481 to 16503, 16506 to 16579, 16582 to 16620, 16622 to 16698, 16700 to 16716, 16723 to 16771, 16786 to 16816, 16835 to 16864, 16865 to 16878, 16872 to 16888, 16890 to 16906, 16904 to 16938, 16965 to 17052, 17054 to 17069, 17071 to 17085, 17083 to 17098, 17088 to 17111, 17124 to 17138, 17140 to 17159, 17181 to 17202, 17202 to 17218, 17229 to 17248, 17250 to 17268, 17332 to 17349, 17363 to 17387, 17389 to 17429, 17450 to 17464, 17482 to 17497, 18104 to 18117, 18418 to 18431, 18613 to 18626, 18620 to 18634, 18707 to 18721, 18841 to 18855, 18875 to 18889, 19282 to 19295, 19310 to 19323, 19454 to 19467, 19774 to 19792, 19794 to 19864, 19862 to 19890, 19892 to 19918, 19907 to 19931, 19927 to 19942, 19932 to 19971, 19973 to 20011, 20022 to 20063, 20080 to 20093, 20131 to 20144, 20240 to 20253, 20448 to 20463, 20495 to 20508, 20532 to 20545, 20600 to 20613, 20617 to 20630, 20960 to 20977, 21412 to 21428, 21465 to 21479, 21489 to 21508, 21797 to 21812, 22015 to 22030, 22144 to 22157, 22153 to 22167, 22265 to 22278, 23110 to 23123, 23114 to 23133, 23286 to 23303, 23364 to 23379, 23478 to 23498, 23544 to 23587, 23589 to 23630, 23658 to 23676, 23678 to 23702, 23704 to 23729, 23731 to 23748, 23740 to 23755, 23744 to 23757, 23750 to 23764, 23767 to 23795, 23802 to 23816, 23818 to 23831, 23855 to 23869, 23906 to 23926, 23928 to 23942, 23994 to 24007, 24005 to 24018, 24023 to 24056, 24074 to 24088, 24088 to 24104, 24112 to 24163, 24199 to 24212, 24231 to 24244, 24237 to 24252, 24254 to 24267, 24281 to 24325, 24327 to 24353, 24355 to 24374, 24376 to 24399, 24401 to 24416, 24442 to 24489, 24492 to 24506, 24498 to 24511, 24538 to 24556, 24546 to 24562, 24591 to 24618, 24620 to 24633, 24635 to 24650, 24665 to 24681, 24687 to 24706, 24709 to 24729, 24731 to 24752, 24756 to 24771, 24773 to 24788, 24793 to 24821, 24823 to 24854, 24856 to 24870, 24873 to 24922, 24933 to 24954, 24965 to 24984, 25019 to 25052, 25054 to 25099, 25112 to 25125, 25133 to 25169, 25171 to 25184, 25186 to 25221, 25236 to 25253, 25246 to 25296, 25298 to 25336, 25332 to 25348, 25349 to 25363, 25388 to 25432, 25439 to 25462, 25509 to 25523, 25525 to 25547, 25578 to 25593, 25587 to 25601, 25604 to 25617, 25633 to 25655, 25672 to 25716, 25725 to 25738, 25764 to 25800, 25802 to 25828, 25831 to 25846, 25851 to 25872, 25877 to 25904, 25921 to 25946, 25943 to 25970, 25972 to 25986, 26051 to 26064, 26068 to 26086, 26113 to 26137, 26139 to 26159, 26182 to 26197, 26243 to 26296, 26298 to 26313, 26327 to 26350, 26366 to 26385, 26387 to 26404, 26397 to 26415, 26416 to 26453, 26447 to 26461, 26457 to 26471, 26481 to 26498, 26502 to 26525, 26528 to 26562, 26564 to 26590, 26590 to 26622, 26624 to 26638, 26687 to 26702, 26706 to 26719, 26717 to 26730, 26729 to 26743, 26767 to 26797, 26796 to 26816, 26831 to 26847, 26837 to 26850, 26877 to 26890, 26900 to 26922, 26911 to 26933, 26933 to 26946, 26938 to 26977, 26979 to 26992, 26981 to 27017, 27023 to 27041, 27039 to 27055, 27075 to 27121, 27138 to 27153, 27163 to 27266, 27270 to 27293, 27325 to 27358, 27363 to 27408, 27419 to 27448, 27450 to 27469, 27471 to 27498, 27510 to 27523, 27535 to 27562, 28098 to 28119, 28136 to 28155, 28169 to 28197, 28199 to 28212, 28221 to 28244, 28271 to 28285, 28400 to 28414, 28441 to 28476, 28490 to 28533, 28535 to 28562, 28575 to 28600, 28621 to 28634, 28650 to 28663, 28674 to 28687, 28681 to 28699, 28713 to 28730, 28736 to 28761, 28763 to 28811, 28821 to 28854, 28856 to 28881, 28883 to 28920, 28922 to 28947, 28979 to 29006, 29008 to 29056, 29078 to 29095, 29098 to 29129, 29122 to 29135, 29131 to 29144, 29144 to 29158, 29160 to 29207, 29209 to 29230, 29234 to 29266, 29268 to 29286, 29301 to 29315, 29304 to 29323, 29330 to 29352, 29344 to 29358, 29347 to 29365, 29377 to 29402, 29402 to 29422, 29424 to 29445, 29443 to 29457, 29447 to 29460, 29462 to 29475, 29491 to 29512, 29514 to 29551, 29547 to 29560, 29553 to 29620, 29625 to 29700, 29714 to 29745, 29774 to 29805, 29816 to 29847, 29875 to 29892, 29894 to 29908, 29897 to 29910, 29917 to 29938, 29939 to 29952, 29961 to 29976, 29974 to 29987, 29978 to 30001, 30006 to 30023, 30025 to 30039, 30043 to 30107, 30145 to 30158, 30149 to 30166, 30173 to 30228, 30230 to 30250, 30251 to 30309, 30321 to 30358, 30359 to 30380, 30382 to 30422, 30428 to 30442, 30455 to 30482, 30484 to 30498, 30516 to 30531, 30533 to 30646, 30654 to 30745, 30745 to 30760, 30752 to 30766, 30788 to 30843, 30845 to 30867, 30869 to 30912, 30906 to 30920, 30934 to 30951, 30962 to 30984, 30989 to 31002, 31010 to 31033, 31036 to 31062, 31092 to 31106, 31128 to 31166, 31168 to 31182, 31189 to 31203, 31205 to 31218, 31224 to 31253, 31256 to 31272, 31274 to 31292, 31294 to 31322, 31324 to 31353, 31357 to 31370, 31373 to 31399, 31403 to 31426, 31445 to 31460, 31463 to 31483, 31485 to 31501, 31494 to 31508, 31507 to 31529, 31531 to 31565, 31567 to 31615, 31630 to 31665, 31675 to 31691, 31703 to 31721, 31729 to 31769, 31770 to 31790, 31795 to 31813, 31815 to 31835, 31837 to 31865, 31876 to 31889, 31920 to 31945, 31962 to 31978, 31983 to 32014, 32029 to 32050, 32058 to 32110, 32129 to 32147, 32166 to 32242, 32244 to 32279, 32296 to 32315, 32334 to 32396, 32398 to 32425, 32427 to 32453, 32459 to 32481, 32475 to 32498, 32490 to 32523, 32519 to 32534, 32525 to 32547, 32542 to 32555, 32559 to 32572, 32574 to 32587, 32595 to 32618, 32613 to 32626, 32627 to 32649, 32651 to 32664, 32655 to 32689, 32693 to 32719, 32721 to 32750, 32752 to 32778, 32780 to 32795, 32797 to 32847, 32881 to 32894, 32891 to 32904, 32896 to 32911, 32927 to 32972, 32986 to 33017, 33019 to 33036, 33038 to 33096, 33102 to 33123, 33132 to 33145, 33150 to 33163, 33166 to 33199, 33214 to 33260, 33262 to 33292, 33294 to 33307, 33316 to 33351, 33360 to 33402, 33412 to 33425, 33427 to 33442, 33439 to 33452, 33443 to 33456, 33460 to 33501, 33503 to 33535, 33542 to 33557, 34168 to 34181, 34370 to 34385, 35422 to 35435, 35627 to 35641, 35685 to 35700, 35837 to 35851, 35849 to 35864, 35866 to 35879, 35974 to 35987, 36009 to 36042, 36044 to 36079, 36081 to 36097, 36099 to 36120, 36119 to 36133, 36147 to 36163, 36171 to 36200, 36216 to 36241, 36245 to 36274, 36265 to 36283, 36295 to 36348, 36352 to 36389, 36383 to 36400, 36402 to 36419, 36475 to 36520, 36522 to 36539, 36541 to 36626, 36652 to 36672, 36675 to 36705, 36707 to 36746, 36780 to 36808, 36810 to 36823, 36825 to 36901, 36903 to 36922, 36924 to 36982, 36999 to 37030, 37056 to 37083, 37091 to 37135, 37194 to 37221, 37238 to 37277, 37280 to 37294, 37298 to 37315, 37325 to 37350, 37363 to 37383, 37377 to 37394, 37384 to 37397, 37390 to 37438, 37456 to 37481, 37478 to 37491, 37481 to 37503, 37506 to 37524, 37526 to 37545, 37540 to 37572, 37574 to 37590, 37601 to 37616, 37621 to 37658, 37673 to 37690, 37703 to 37738, 37740 to 37753, 37764 to 37790, 37800 to 37818, 37820 to 37850, 37888 to 37909, 37911 to 37972, 37986 to 38014, 38016 to 38032, 38034 to 38053, 38055 to 38073, 38075 to 38090, 38092 to 38128, 38141 to 38167, 38171 to 38194, 38213 to 38240, 38264 to 38286, 38288 to 38370, 38394 to 38420, 38452 to 38467, 38471 to 38487, 38477 to 38490, 38494 to 38507, 38536 to 38556, 38580 to 38593, 38602 to 38618, 38628 to 38654, 38693 to 38709, 38709 to 38722, 38711 to 38725, 38740 to 38756, 38749 to 38769, 38772 to 38797, 38827 to 38846, 38860 to 38883, 38885 to 38905, 38911 to 38931, 38933 to 38949, 38962 to 39032, 39034 to 39047, 39049 to 39070, 39075 to 39115, 39127 to 39143, 39148 to 39162, 39164 to 39222, 39218 to 39231, 39224 to 39256, 39265 to 39306, 39297 to 39311, 39308 to 39343, 39345 to 39359, 39361 to 39381, 39370 to 39383, 39383 to 39399, 39417 to 39469, 39490 to 39503, 39500 to 39522, 39535 to 39549, 39551 to 39611, 39628 to 39647, 39649 to 39690, 39707 to 39759, 39773 to 39797, 39799 to 39858, 39872 to 39928, 39930 to 39969, 39973 to 39997, 39998 to 40013, 40015 to 40064, 40067 to 40108, 40110 to 40140, 40147 to 40163, 40154 to 40179, 40181 to 40196, 40232 to 40282, 40284 to 40307, 40309 to 40368, 40381 to 40399, 40431 to 40471, 40479 to 40493, 40484 to 40522, 40524 to 40544, 40547 to 40561, 40577 to 40594, 40586 to 40599, 40616 to 40631, 40634 to 40647, 40674 to 40727, 40738 to 40755, 40749 to 40771, 40780 to 40802, 40811 to 40834, 40847 to 40865, 40861 to 40875, 40869 to 40897, 40899 to 40919, 40921 to 40939, 40942 to 40962, 40967 to 40980, 41008 to 41097, 41099 to 41131, 41133 to 41200, 41202 to 41223, 41225 to 41242, 41266 to 41279, 41275 to 41298, 41300 to 41321, 41325 to 41360, 41367 to 41388, 41403 to 41421, 41439 to 41462, 41481 to 41496, 41508 to 41523, 41531 to 41550, 41552 to 41590, 41590 to 41603, 41612 to 41662, 41664 to 41688, 41685 to 41698, 41691 to 41716, 41718 to 41764, 41761 to 41776, 41778 to 41809, 41798 to 41811, 41838 to 41866, 41872 to 41893, 41885 to 41898, 41912 to 41925, 41914 to 41930, 41923 to 41942, 41933 to 41956, 41962 to 41978, 41997 to 42012, 42026 to 42042, 42035 to 42048, 42037 to 42050, 42048 to 42064, 42056 to 42079, 42081 to 42095, 42096 to 42139, 42141 to 42187, 42190 to 42226, 42232 to 42253, 42255 to 42305, 42307 to 42320, 42347 to 42375, 42389 to 42425, 42427 to 42442, 42452 to 42474, 42482 to 42496, 42495 to 42509, 42536 to 42550, 42566 to 42580, 42590 to 42612, 42646 to 42678, 42683 to 42723, 42735 to 42750, 42752 to 42817, 42843 to 42873, 42890 to 42939, 42938 to 42989, 42991 to 43005, 43007 to 43020, 43036 to 43055, 43057 to 43102, 43113 to 43145, 43147 to 43180, 43204 to 43221, 43221 to 43265, 43267 to 43296, 43311 to 43334, 43336 to 43361, 43371 to 43395, 43399 to 43423, 43425 to 43453, 43452 to 43468, 43470 to 43488, 43495 to 43522, 43525 to 43559, 43561 to 43584, 43590 to 43611, 43618 to 43650, 43670 to 43685, 43722 to 43774, 43776 to 43791, 43808 to 43835, 43835 to 43851, 43853 to 43868, 43923 to 43937, 43952 to 43987, 44011 to 44029, 44028 to 44070, 44072 to 44094, 44101 to 44130, 44137 to 44205, 44224 to 44244, 44246 to 44265, 44267 to 44318, 44316 to 44336, 44338 to 44359, 44361 to 44424, 44439 to 44474, 44476 to 44500, 44502 to 44519, 44539 to 44553, 44563 to 44578, 44585 to 44599, 44601 to 44617, 44640 to 44701, 44704 to 44723, 44741 to 44763, 44766 to 44846, 44870 to 44889, 44887 to 44905, 44920 to 44947, 44949 to 44966, 44994 to 45022, 45042 to 45059, 45061 to 45087, 45116 to 45154, 45156 to 45182, 45183 to 45198, 45210 to 45243, 45245 to 45320, 45331 to 45367, 45380 to 45399, 45415 to 45428, 45421 to 45486, 45488 to 45545, 45556 to 45576, 45578 to 45597, 45603 to 45650, 45652 to 45665, 45675 to 45715, 45749 to 45763, 45804 to 45826, 45839 to 45861, 45878 to 45910, 45926 to 45954, 45956 to 45975, 45977 to 45997, 45999 to 46020, 46046 to 46063, 46065 to 46088, 46097 to 46118, 46120 to 46142, 46144 to 46160, 46162 to 46185, 46204 to 46280, 46302 to 46326, 46328 to 46355, 46358 to 46377, 46379 to 46436, 46457 to 46471, 46473 to 46492, 46501 to 46541, 46543 to 46572, 46584 to 46626, 46655 to 46683, 46685 to 46702, 46704 to 46722, 46724 to 46763, 46784 to 46800, 46802 to 46827, 46830 to 46867, 46869 to 46887, 46889 to 46920, 46922 to 46947, 46976 to 47009, 47011 to 47030, 47032 to 47064, 47066 to 47092, 47108 to 47130, 47132 to 47168, 47170 to 47199, 47201 to 47222, 47238 to 47277, 47296 to 47350, 47352 to 47391, 47416 to 47440, 47452 to 47466, 47468 to 47523, 47522 to 47546, 47548 to 47567, 47569 to 47595, 47597 to 47634, 47657 to 47693, 47712 to 47731, 47749 to 47762, 47771 to 47825, 47827 to 47846, 47848 to 47872, 47874 to 47888, 47890 to 47909, 47911 to 47925, 47927 to 47952, 47961 to 47993, 48001 to 48016, 48051 to 48083, 48096 to 48158, 48158 to 48176, 48186 to 48201, 48213 to 48239, 48241 to 48256, 48258 to 48278, 48280 to 48339, 48341 to 48357, 48359 to 48377, 48379 to 48393, 48395 to 48488, 48492 to 48510, 48528 to 48549, 48550 to 48589, 48636 to 48658, 48683 to 48697, 48699 to 48762, 48762 to 48775, 48773 to 48832, 48873 to 48886, 48888 to 48914, 48916 to 48944, 48969 to 49008, 49010 to 49024, 49051 to 49110, 49116 to 49150, 49151 to 49184, 49187 to 49200, 49213 to 49230, 49233 to 49247, 49267 to 49284, 49297 to 49310, 49317 to 49369, 49371 to 49435, 49444 to 49458, 49467 to 49500, 49510 to 49538, 49540 to 49559, 49561 to 49584, 49591 to 49626, 49628 to 49646, 49653 to 49737, 49787 to 49802, 49817 to 49835, 49841 to 49860, 49862 to 49883, 49885 to 49905, 49921 to 49950, 49961 to 49979, 49995 to 50051, 50053 to 50071, 50073 to 50088, 50132 to 50158, 50167 to 50183, 50201 to 50226, 50226 to 50239, 50259 to 50313, 50323 to 50341, 50343 to 50396, 50390 to 50403, 50398 to 50448, 50451 to 50483, 50489 to 50507, 50526 to 50548, 50550 to 50569, 50575 to 50602, 50606 to 50621, 50617 to 50630, 50623 to 50641, 50634 to 50647, 50644 to 50663, 50665 to 50684, 50705 to 50730, 50732 to 50763, 50766 to 50799, 50797 to 50823, 50838 to 50864, 50870 to 50884, 50885 to 50911, 50924 to 50937, 50939 to 50974, 50980 to 51008, 51015 to 51030, 51034 to 51047, 51075 to 51089, 51109 to 51123, 51135 to 51172, 51189 to 51216, 51241 to 51260, 51273 to 51294, 51296 to 51312, 51337 to 51357, 51356 to 51381, 51393 to 51465, 51476 to 51494, 51496 to 51515, 51530 to 51544, 51546 to 51572, 51586 to 51600, 51602 to 51617, 51619 to 51677, 51679 to 51700, 51727 to 51741, 51743 to 51821, 51826 to 51859, 51884 to 51912, 51918 to 51936, 51947 to 51979, 52004 to 52017, 52023 to 52048, 52141 to 52167, 52169 to 52188, 52204 to 52225, 52246 to 52262, 52289 to 52306, 52321 to 52339, 52341 to 52360, 52360 to 52428, 52430 to 52504, 52506 to 52567, 52579 to 52594, 52591 to 52610, 52612 to 52642, 52644 to 52667, 52672 to 52686, 52688 to 52702, 52715 to 52753, 52770 to 52783, 52779 to 52792, 52814 to 52845, 52834 to 52857, 52858 to 52885, 52887 to 52943, 52945 to 52962, 52971 to 53019, 53011 to 53036, 53053 to 53066, 53092 to 53112, 53124 to 53151, 53161 to 53175, 53184 to 53220, 53222 to 53243, 53245 to 53260, 53278 to 53304, 53311 to 53346, 53364 to 53386, 53388 to 53404, 53417 to 53431, 53449 to 53463, 53465 to 53484, 53514 to 53527, 53552 to 53567, 53570 to 53591, 53618 to 53644, 53645 to 53667, 53669 to 53684, 53714 to 53742, 53744 to 53764, 53818 to 53843, 53845 to 53860, 53875 to 53889, 53961 to 53991, 53991 to 54013, 54015 to 54055, 54057 to 54081, 54114 to 54135, 54163 to 54178, 54180 to 54193, 54195 to 54254, 54261 to 54290, 54292 to 54307, 54309 to 54327, 54357 to 54372, 54404 to 54420, 54418 to 54439, 54441 to 54466, 54468 to 54512, 54519 to 54532, 54555 to 54572, 54588 to 54601, 54609 to 54633, 54644 to 54688, 54690 to 54721, 54723 to 54761, 54786 to 54802, 54819 to 54835, 54837 to 54912, 54924 to 54941, 54999 to 55017, 55019 to 55035, 55060 to 55073, 55075 to 55100, 55129 to 55171, 55173 to 55188, 55190 to 55203, 55210 to 55230, 55233 to 55281, 55276 to 55289, 55283 to 55320, 55330 to 55379, 55381 to 55423, 55420 to 55441, 55486 to 55502, 55515 to 55533, 55535 to 55553, 55555 to 55569, 55569 to 55588, 55590 to 55611, 55615 to 55663, 55665 to 55678, 55696 to 55713, 55715 to 55738, 55744 to 55774, 55776 to 55794, 55801 to 55823, 55862 to 55906, 55920 to 55933, 55922 to 55947, 55974 to 55993, 55990 to 56031, 56045 to 56073, 56082 to 56114, 56117 to 56140, 56183 to 56214, 56218 to 56236, 56261 to 56282, 56311 to 56336, 56331 to 56345, 56338 to 56358, 56369 to 56390, 56391 to 56431, 56433 to 56451, 56453 to 56473, 56475 to 56498, 56500 to 56546, 56558 to 56581, 56584 to 56597, 56611 to 56647, 56643 to 56657, 56667 to 56691, 56732 to 56759, 56788 to 56805, 56821 to 56845, 56850 to 56882, 56885 to 56906, 56928 to 56942, 56944 to 56959, 56961 to 56975, 56984 to 57002, 57004 to 57041, 57057 to 57082, 57084 to 57122, 57162 to 57222, 57224 to 57246, 57259 to 57284, 57317 to 57332, 57346 to 57369, 57388 to 57423, 57425 to 57440, 57442 to 57455, 57475 to 57492, 57508 to 57522, 57522 to 57546, 57548 to 57576, 57593 to 57634, 57658 to 57675, 57687 to 57771, 57786 to 57803, 57801 to 57819, 57830 to 57858, 57889 to 57911, 57926 to 57945, 57947 to 57972, 58009 to 58028, 58030 to 58060, 58063 to 58091, 58124 to 58146, 58147 to 58162, 58163 to 58198, 58214 to 58292, 58292 to 58309, 58336 to 58429, 58436 to 58457, 58453 to 58501, 58525 to 58553, 58566 to 58579, 58571 to 58584, 58586 to 58601, 58604 to 58630, 58656 to 58682, 58696 to 58713, 58722 to 58744, 58757 to 58771, 58805 to 58979, 58987 to 59073, 59072 to 59123, 59124 to 59150, 59154 to 59234, 59231 to 59276, 59291 to 59413, 59413 to 59458, 59466 to 59511, 59513 to 59533, 59549 to 59764, 59762 to 59825, 59824 to 59907, 59916 to 60004, 60006 to 60030, 60027 to 60040, 60032 to 60100, 60119 to 60188, 60191 to 60227, 60220 to 60287, 60289 to 60314, 60316 to 60554, 60556 to 60575, 60579 to 60593, 60595 to 60638, 60651 to 60690, 60692 to 60724, 60716 to 60799, 60801 to 60872, 60868 to 60881, 60885 to 60912, 60961 to 61009, 61014 to 61042, 61046 to 61059, 61053 to 61066, 61061 to 61084, 61134 to 61164, 61178 to 61199, 61201 to 61229, 61258 to 61284, 61286 to 61304, 61316 to 61332, 61341 to 61354, 61356 to 61383, 61407 to 61440, 61451 to 61468, 61470 to 61497, 61493 to 61506, 61499 to 61529, 61531 to 61558, 61590 to 61615, 61623 to 61640, 61673 to 61877, 61879 to 61898, 61900 to 61941, 61943 to 61962, 61964 to 61983, 62003 to 62017, 62015 to 62080, 62100 to 62124, 62133 to 62146, 62139 to 62175, 62191 to 62237, 62250 to 62270, 62283 to 62316, 62310 to 62358, 62357 to 62397, 62399 to 62413, 62415 to 62470, 62472 to 62501, 62503 to 62541, 62553 to 62609, 62611 to 62656, 62663 to 62690, 62703 to 62735, 62737 to 62759, 62765 to 62789, 62802 to 62816, 62810 to 62824, 62853 to 62868, 62864 to 62878, 62878 to 62907, 62905 to 62937, 62937 to 62951, 62943 to 62956, 62946 to 62960, 62961 to 62988, 62993 to 63006, 63005 to 63019, 63030 to 63049, 63057 to 63076, 63073 to 63088, 63078 to 63125, 63128 to 63152, 63154 to 63170, 63172 to 63196, 63185 to 63223, 63225 to 63245, 63236 to 63254, 63245 to 63261, 63263 to 63276, 63280 to 63295, 63292 to 63336, 63344 to 63368, 63369 to 63396, 63385 to 63398, 63395 to 63417, 63433 to 63451, 63440 to 63453, 63454 to 63470, 63472 to 63511, 63513 to 63539, 63547 to 63603, 63625 to 63651, 63676 to 63692, 63730 to 63746, 63759 to 63775, 63779 to 63833, 63844 to 63883, 63889 to 63907, 63910 to 63938, 63943 to 63962, 64004 to 64033, 64056 to 64087, 64112 to 64132, 64142 to 64158, 64160 to 64191, 64193 to 64209, 64214 to 64227, 64228 to 64241, 64254 to 64278, 64280 to 64298, 64300 to 64338, 64340 to 64355, 64357 to 64380, 64412 to 64434, 64438 to 64456, 64458 to 64488, 64490 to 64517, 64519 to 64538, 64552 to 64572, 64585 to 64608, 64625 to 64642, 64631 to 64644, 64644 to 64683, 64703 to 64716, 64736 to 64751, 64759 to 64773, 64775 to 64806, 64815 to 64831, 64845 to 64878, 64880 to 64904, 64915 to 64937, 64948 to 64971, 64973 to 64994, 64996 to 65017, 65019 to 65055, 65062 to 65109, 65111 to 65138, 65140 to 65179, 65181 to 65195, 65210 to 65230, 65232 to 65248, 65271 to 65296, 65298 to 65319, 65321 to 65371, 65391 to 65413, 65415 to 65436, 65436 to 65454, 65477 to 65490, 65492 to 65520, 65522 to 65552, 65554 to 65579, 65581 to 65594, 65591 to 65606, 65595 to 65616, 65618 to 65632, 65634 to 65657, 65661 to 65716, 65730 to 65747, 65748 to 65807, 65809 to 65829, 65831 to 65844, 65846 to 65859, 65861 to 65891, 65898 to 65920, 65930 to 65963, 65980 to 66060, 66069 to 66085, 66095 to 66108, 66110 to 66126, 66139 to 66173, 66175 to 66191, 66204 to 66226, 66224 to 66263, 66265 to 66278, 66280 to 66320, 66322 to 66345, 66355 to 66371, 66375 to 66407, 66411 to 66424, 66421 to 66441, 66440 to 66460, 66463 to 66482, 66484 to 66501, 66509 to 66527, 66534 to 66548, 66556 to 66569, 66562 to 66593, 66606 to 66637, 66639 to 66665, 66674 to 66690, 66692 to 66720, 66722 to 66742, 66758 to 66786, 66787 to 66802, 66812 to 66862, 66864 to 66885, 66940 to 66953, 66982 to 66997, 67024 to 67084, 67103 to 67118, 67156 to 67185, 67181 to 67195, 67193 to 67206, 67215 to 67229, 67231 to 67271, 67288 to 67301, 67294 to 67345, 67362 to 67379, 67381 to 67397, 67409 to 67448, 67468 to 67481, 67483 to 67510, 67540 to 67561, 67620 to 67640, 67656 to 67672, 67674 to 67749, 67751 to 67764, 67783 to 67801, 67803 to 67828, 67830 to 67848, 67850 to 67868, 67877 to 67918, 67933 to 67961, 67963 to 67978, 67998 to 68026, 68028 to 68046, 68048 to 68082, 68084 to 68112, 68114 to 68130, 68129 to 68155, 68170 to 68192, 68194 to 68237, 68239 to 68261, 68272 to 68286, 68290 to 68373, 68375 to 68419, 68442 to 68487, 68489 to 68547, 68549 to 68592, 68599 to 68614, 68617 to 68657, 68659 to 68686, 68688 to 68735, 68732 to 68747, 68749 to 68786, 68788 to 68830, 68837 to 68879, 68882 to 68899, 68918 to 68942, 68944 to 68968, 68983 to 69007, 69012 to 69027, 69020 to 69064, 69064 to 69077, 69079 to 69114, 69116 to 69196, 69185 to 69198, 69202 to 69219, 69228 to 69246, 69240 to 69282, 69294 to 69317, 69306 to 69324, 69333 to 69346, 69352 to 69366, 69387 to 69431, 69433 to 69447, 69452 to 69480, 69482 to 69497, 69491 to 69504, 69511 to 69564, 69566 to 69628, 69628 to 69642, 69659 to 69681, 69684 to 69697, 69719 to 69744, 69746 to 69763, 69765 to 69792, 69801 to 69828, 69853 to 69901, 69933 to 69949, 69951 to 69966, 69968 to 69983, 69988 to 70061, 70083 to 70100, 70110 to 70154, 70161 to 70199, 70202 to 70225, 70231 to 70246, 70269 to 70295, 70292 to 70327, 70331 to 70349, 70351 to 70371, 70381 to 70403, 70405 to 70420, 70422 to 70483, 70496 to 70533, 70535 to 70578, 70577 to 70639, 70653 to 70667, 70661 to 70674, 70669 to 70695, 70687 to 70705, 70708 to 70744, 70746 to 70764, 70766 to 70779, 70781 to 70832, 70834 to 70851, 70858 to 70887, 70889 to 70902, 70920 to 70933, 70935 to 70964, 70974 to 70987, 71008 to 71028, 71030 to 71046, 71048 to 71073, 71075 to 71106, 71108 to 71133, 71137 to 71152, 71153 to 71170, 71179 to 71192, 71197 to 71224, 71235 to 71251, 71253 to 71311, 71310 to 71329, 71330 to 71364, 71366 to 71386, 71388 to 71410, 71412 to 71433, 71448 to 71472, 71475 to 71491, 71491 to 71553, 71555 to 71581, 71583 to 71624, 71634 to 71700, 71706 to 71725, 71732 to 71747, 71789 to 71804, 71810 to 71824, 71819 to 71834, 71839 to 71872, 71876 to 71889, 71886 to 71908, 71910 to 71924, 71985 to 71999, 72000 to 72021, 72023 to 72047, 72071 to 72158, 72165 to 72192, 72194 to 72234, 72236 to 72255, 72257 to 72281, 72283 to 72299, 72312 to 72329, 72323 to 72336, 72348 to 72395, 72398 to 72411, 72413 to 72455, 72470 to 72503, 72506 to 72541, 72545 to 72558, 72560 to 72586, 72583 to 72597, 72588 to 72602, 72611 to 72636, 72638 to 72688, 72696 to 72736, 72738 to 72761, 72774 to 72799, 72801 to 72886, 72888 to 72903, 72928 to 72958, 72962 to 72990, 73001 to 73014, 73017 to 73053, 73055 to 73078, 73077 to 73090, 73088 to 73121, 73124 to 73153, 73147 to 73172, 73164 to 73203, 73218 to 73257, 73260 to 73273, 73268 to 73281, 73278 to 73291, 73298 to 73313, 73451 to 73465, 73459 to 73472, 73512 to 73567, 73569 to 73611, 73614 to 73645, 73661 to 73713, 73712 to 73727, 73716 to 73731, 73735 to 73748, 73741 to 73760, 73764 to 73782, 73783 to 73801, 73795 to 73829, 73860 to 73873, 73885 to 73904, 73906 to 73919, 73916 to 73945, 73947 to 73961, 73978 to 74018, 74020 to 74046, 74061 to 74082, 74092 to 74158, 74160 to 74177, 74179 to 74209, 74216 to 74245, 74270 to 74287, 74289 to 74305, 74307 to 74368, 74369 to 74411, 74416 to 74461, 74463 to 74479, 74506 to 74541, 74543 to 74636, 74647 to 74704, 74745 to 74770, 74789 to 74813, 74815 to 74838, 74850 to 74877, 74891 to 74923, 74925 to 74940, 74952 to 74969, 74979 to 75001, 75037 to 75066, 75068 to 75088, 75097 to 75123, 75131 to 75149, 75152 to 75189, 75210 to 75252, 75254 to 75276, 75288 to 75310, 75338 to 75357, 75359 to 75372, 75376 to 75397, 75405 to 75432, 75440 to 75470, 75482 to 75501, 75503 to 75540, 75544 to 75560, 75562 to 75576, 75589 to 75610, 75633 to 75646, 75648 to 75679, 75691 to 75709, 75711 to 75724, 75740 to 75764, 75763 to 75776, 75767 to 75790, 75780 to 75794, 75792 to 75808, 75810 to 75829, 75831 to 75863, 75865 to 75880, 75882 to 75922, 75932 to 75998, 76000 to 76026, 76028 to 76045, 76046 to 76082, 76098 to 76413, 76420 to 76442, 76456 to 76477, 76484 to 76558, 76573 to 76592, 76608 to 76622, 76627 to 76663, 76665 to 76683, 76685 to 76698, 76702 to 76716, 76725 to 76744, 76745 to 76761, 76780 to 76796, 76798 to 76812, 76814 to 76832, 76834 to 76859, 76871 to 76934, 77012 to 77034, 77039 to 77055, 77081 to 77094, 77121 to 77184, 77186 to 77200, 77202 to 77225, 77227 to 77247, 77261 to 77317, 77327 to 77340, 77342 to 77366, 77377 to 77394, 77396 to 77439, 77453 to 77468, 77462 to 77593, 77586 to 77599, 77595 to 77641, 77643 to 77728, 77730 to 77768, 77778 to 77816, 77818 to 77835, 77837 to 77855, 77861 to 77876, 77882 to 77898, 77900 to 77924, 77923 to 77936, 77957 to 77970, 77962 to 77985, 77994 to 78022, 78024 to 78056, 78079 to 78128, 78132 to 78158, 78173 to 78213, 78224 to 78265, 78275 to 78332, 78334 to 78440, 78442 to 78489, 78491 to 78505, 78501 to 78514, 78507 to 78537, 78557 to 78570, 78562 to 78623, 78625 to 78665, 78668 to 78684, 78686 to 78759, 78761 to 78787, 78793 to 78814, 78816 to 78854, 78847 to 78860, 78874 to 78909, 78917 to 78944, 78956 to 78978, 78991 to 79008, 79003 to 79032, 79026 to 79040, 79044 to 79072, 79098 to 79158, 79162 to 79182, 79184 to 79228, 79221 to 79235, 79230 to 79262, 79287 to 79333, 79356 to 79392, 79441 to 79476, 79488 to 79522, 79522 to 79539, 79568 to 79583, 79574 to 79601, 79603 to 79618, 79617 to 79639, 79651 to 79683, 79685 to 79724, 79721 to 79736, 79727 to 79782, 79784 to 79812, 79809 to 79834, 79841 to 79861, 79873 to 79923, 79928 to 79948, 79950 to 79986, 79993 to 80019, 80019 to 80063, 80071 to 80088, 80114 to 80160, 80154 to 80183, 80185 to 80212, 80214 to 80232, 80240 to 80266, 80293 to 80312, 80344 to 80380, 80382 to 80420, 80410 to 80423, 80417 to 80438, 80440 to 80456, 80467 to 80499, 80501 to 80527, 80532 to 80561, 80563 to 80599, 80604 to 80692, 80702 to 80737, 80739 to 80795, 80796 to 80871, 80873 to 80891, 80925 to 80961, 80963 to 80992, 81009 to 81068, 81070 to 81150, 81156 to 81199, 81201 to 81225, 81237 to 81253, 81255 to 81271, 81292 to 81351, 81353 to 81371, 81392 to 81422, 81438 to 81483, 81485 to 81503, 81512 to 81526, 81532 to 81554, 81556 to 81593, 81606 to 81664, 81666 to 81698, 81701 to 81720, 81728 to 81776, 81781 to 81810, 81812 to 81847, 81849 to 81893, 81908 to 81934, 81943 to 81964, 81967 to 82034, 82036 to 82134, 82136 to 82154, 82176 to 82197, 82199 to 82250, 82252 to 82269, 82271 to 82293, 82300 to 82314, 82329 to 82343, 82344 to 82357, 82378 to 82407, 82406 to 82422, 82421 to 82443, 82446 to 82469, 82490 to 82507, 82502 to 82523, 82547 to 82576, 82590 to 82603, 82628 to 82647, 82650 to 82666, 82669 to 82683, 82685 to 82716, 82715 to 82736, 82760 to 82785, 82778 to 82791, 82780 to 82818, 82811 to 82825, 82821 to 82864, 82883 to 82915, 82919 to 82935, 82930 to 82946, 82937 to 82957, 82959 to 82972, 82974 to 83000, 83020 to 83036, 83038 to 83088, 83090 to 83115, 83120 to 83140, 83142 to 83155, 83160 to 83186, 83198 to 83215, 83227 to 83246, 83273 to 83339, 83341 to 83385, 83387 to 83400, 83413 to 83426, 83417 to 83449, 83486 to 83520, 83522 to 83565, 83567 to 83581, 83576 to 83670, 83681 to 83701, 83703 to 83716, 83733 to 83817, 83817 to 83830, 83832 to 83853, 83855 to 83871, 83886 to 83926, 83958 to 83974, 83976 to 83991, 83993 to 84031, 84033 to 84067, 84069 to 84102, 84104 to 84121, 84143 to 84233, 84249 to 84281, 84283 to 84403, 84404 to 84432, 84431 to 84444, 84434 to 84490, 84503 to 84520, 84522 to 84555, 84557 to 84572, 84574 to 84597, 84607 to 84626, 84650 to 84675, 84677 to 84700, 84721 to 84753, 84755 to 84807, 84809 to 84826, 84831 to 84849, 84879 to 84893, 84895 to 84915, 84917 to 84961, 85234 to 85247, 85253 to 85267, 85256 to 85351, 85359 to 85374, 85363 to 85376, 85365 to 85381, 85380 to 85414, 85416 to 85454, 85456 to 85484, 85509 to 85545, 85535 to 85550, 85566 to 85584, 85586 to 85610, 85604 to 85627, 85628 to 85665, 85698 to 85723, 85713 to 85728, 85722 to 85735, 85770 to 85785, 85800 to 85813, 85875 to 85888, 85950 to 85963, 86097 to 86125, 86127 to 86142, 86175 to 86198, 86226 to 86242, 86237 to 86302, 86308 to 86327, 86321 to 86334, 86329 to 86382, 86384 to 86400, 86403 to 86417, 86414 to 86437, 86439 to 86455, 86461 to 86478, 86473 to 86487, 86480 to 86517, 86517 to 86531, 86565 to 86583, 86600 to 86632, 86634 to 86651, 86653 to 86678, 86697 to 86756, 86782 to 86796, 86786 to 86809, 86811 to 86855, 86857 to 86891, 86894 to 86908, 86916 to 86933, 86945 to 86959, 86951 to 86965, 86969 to 86990, 87017 to 87057, 87059 to 87073, 87062 to 87076, 87066 to 87089, 87097 to 87121, 87110 to 87134, 87130 to 87155, 87160 to 87194, 87185 to 87198, 87209 to 87260, 87257 to 87270, 87274 to 87287, 87276 to 87294, 87294 to 87328, 87317 to 87333, 87336 to 87360, 87368 to 87418, 87441 to 87460, 87462 to 87487, 87489 to 87518, 87520 to 87539, 87542 to 87570, 87572 to 87601, 87603 to 87644, 87642 to 87750, 87756 to 87776, 87778 to 87803, 87803 to 87837, 87872 to 87888, 87890 to 87917, 87949 to 87964, 87963 to 88008, 88010 to 88027, 88029 to 88046, 88048 to 88089, 88091 to 88108, 88110 to 88177, 88179 to 88192, 88194 to 88229, 88234 to 88259, 88261 to 88291, 88303 to 88328, 88328 to 88341, 88340 to 88354, 88356 to 88372, 88411 to 88446, 88448 to 88465, 88469 to 88511, 88518 to 88533, 88531 to 88557, 88547 to 88560, 88573 to 88593, 88597 to 88618, 88620 to 88690, 88692 to 88745, 88954 to 88973, 88988 to 89047, 89066 to 89091, 89098 to 89119, 89135 to 89149, 89151 to 89181, 89177 to 89193, 89223 to 89273, 89285 to 89300, 89315 to 89383, 89404 to 89442, 89444 to 89541, 89579 to 89639, 89660 to 89692, 89694 to 89741, 89773 to 89787, 89789 to 89817, 89826 to 89888, 89904 to 89922, 89937 to 89950, 89945 to 89958, 89956 to 89974, 89971 to 89985, 89979 to 89992, 89984 to 90000, 89999 to 90014, 90017 to 90041, 90036 to 90049, 90077 to 90093, 90099 to 90128, 90130 to 90155, 90157 to 90200, 90225 to 90256, 90258 to 90293, 90305 to 90318, 90320 to 90352, 90356 to 90370, 90400 to 90421, 90423 to 90461, 90464 to 90507, 90509 to 90530, 90529 to 90542, 90531 to 90567, 90569 to 90612, 90614 to 90730, 90732 to 90758, 90760 to 90885, 90887 to 90918, 90920 to 90946, 90938 to 90955, 90960 to 90973, 90965 to 90981, 90973 to 91000, 90997 to 91011, 91002 to 91019, 91059 to 91140, 91142 to 91157, 91157 to 91194, 91196 to 91231, 91233 to 91251, 91253 to 91274, 91296 to 91310, 91335 to 91367, 91406 to 91442, 91447 to 91477, 91489 to 91509, 91520 to 91621, 91623 to 91674, 91680 to 91703, 91715 to 91731, 91733 to 91771, 91773 to 91788, 91790 to 91805, 91807 to 91823, 91825 to 91859, 91861 to 91900, 91907 to 91926, 91928 to 91943, 91950 to 91980, 91982 to 91996, 91998 to 92011, 92010 to 92027, 92027 to 92067, 92069 to 92126, 92128 to 92321, 92323 to 92540, 92542 to 92558, 92566 to 92684, 92686 to 92726, 92728 to 92837, 92839 to 93032, 93034 to 93094, 93100 to 93209, 93211 to 93254, 93256 to 93323, 93325 to 93448, 93459 to 93477, 93475 to 93497, 93509 to 93530, 93532 to 93566, 93568 to 93601, 93606 to 93646, 93668 to 93716, 93718 to 93742, 93744 to 93788, 93790 to 93808, 93811 to 93832, 93874 to 93901, 93904 to 93986, 94021 to 94036, 94038 to 94079, 94073 to 94086, 94097 to 94116, 94118 to 94141, 94140 to 94219, 94242 to 94257, 94264 to 94335, 94337 to 94356, 94358 to 94378, 94373 to 94386, 94384 to 94403, 94405 to 94422, 94453 to 94497, 94497 to 94558, 94560 to 94605, 94630 to 94724, 94739 to 94752, 94755 to 94786, 94800 to 94815, 94872 to 94901, 94903 to 94953, 94955 to 95060, 95070 to 95085, 95093 to 95110, 95135 to 95149, 95154 to 95168, 95170 to 95210, 95227 to 95257, 95302 to 95318, 95311 to 95356, 95359 to 95401, 95403 to 95453, 95450 to 95463, 95475 to 95491, 95503 to 95553, 95555 to 95569, 95583 to 95609, 95634 to 95668, 95718 to 95738, 95727 to 95740, 95836 to 95849, 95851 to 95872, 95874 to 95888, 95890 to 95910, 95912 to 95925, 95938 to 95969, 95973 to 95990, 95992 to 96066, 96073 to 96087, 96103 to 96120, 96122 to 96167, 96169 to 96182, 96183 to 96211, 96213 to 96234, 96246 to 96279, 96300 to 96334, 96358 to 96375, 96377 to 96398, 96424 to 96467, 96496 to 96518, 96520 to 96535, 96540 to 96566, 96572 to 96592, 96604 to 96646, 96642 to 96655, 96648 to 96667, 96681 to 96728, 96730 to 96781, 96804 to 96829, 96831 to 96879, 96887 to 96916, 96928 to 96944, 96946 to 96959, 96970 to 96990, 96992 to 97021, 97023 to 97037, 97039 to 97073, 97075 to 97366, 97368 to 97393, 97420 to 97466, 97469 to 97507, 97513 to 97529, 97531 to 97583, 97585 to 97600, 97602 to 97631, 97633 to 97683, 97685 to 97703, 97705 to 97742, 97787 to 97803, 97805 to 97822, 97824 to 97876, 97878 to 97921, 97923 to 97943, 97945 to 97963, 97965 to 97994, 97995 to 98011, 98014 to 98044, 98039 to 98061, 98055 to 98076, 98077 to 98090, 98079 to 98092, 98085 to 98098, 98100 to 98115, 98113 to 98145, 98142 to 98160, 98162 to 98180, 98188 to 98219, 98215 to 98237, 98227 to 98240, 98232 to 98255, 98255 to 98268, 98264 to 98287, 98292 to 98326, 98373 to 98397, 98399 to 98428, 98442 to 98461, 98480 to 98501, 98499 to 98520, 98524 to 98538, 98537 to 98550, 98545 to 98585, 98595 to 98610, 98599 to 98624, 98644 to 98668, 98678 to 98704, 98703 to 98718, 98736 to 98754, 98778 to 98794, 98802 to 98821, 98845 to 98876, 98878 to 98900, 98900 to 98972, 98961 to 98976, 98974 to 98998, 99011 to 99029, 99033 to 99065, 99067 to 99107, 99151 to 99186, 99188 to 99219, 99222 to 99245, 99254 to 99276, 99288 to 99312, 99314 to 99338, 99367 to 99430, 99444 to 99491, 99496 to 99554, 99570 to 99585, 99587 to 99618, 99620 to 99669, 99679 to 99710, 99720 to 99748, 99750 to 99763, 99768 to 99805, 99818 to 99841, 99855 to 99879, 99881 to 99900, 99902 to 99932, 99934 to 99954, 99959 to 100011, 100011 to 100037, 100057 to 100071, 100073 to 100102, 100104 to 100118, 100131 to 100186, 100188 to 100201, 100194 to 100212, 100214 to 100277, 100279 to 100303, 100309 to 100355, 100349 to 100386, 100379 to 100393, 100388 to 100401, 100403 to 100423, 100452 to 100473, 100508 to 100542, 100548 to 100580, 100582 to 100612, 100614 to 100652, 100695 to 100714, 100736 to 100749, 100751 to 100790, 100808 to 100842, 100844 to 100860, 100862 to 100930, 100939 to 100953, 100955 to 100971, 100973 to 101003, 101021 to 101048, 101057 to 101093, 101109 to 101148, 101145 to 101189, 101194 to 101208, 101210 to 101244, 101256 to 101271, 101277 to 101300, 101310 to 101327, 101329 to 101345, 101374 to 101397, 101409 to 101426, 101453 to 101466, 101474 to 101487, 101481 to 101515, 101518 to 101541, 101542 to 101560, 101554 to 101591, 101593 to 101609, 101635 to 101695, 101707 to 101746, 101748 to 101763, 101774 to 101810, 101812 to 101828, 101819 to 101835, 101829 to 101842, 101842 to 101855, 101857 to 101878, 101880 to 101943, 101947 to 101981, 101988 to 102009, 102022 to 102066, 102068 to 102084, 102100 to 102113, 102115 to 102130, 102132 to 102145, 102192 to 102241, 102269 to 102285, 102312 to 102327, 102357 to 102392, 102407 to 102428, 102430 to 102444, 102460 to 102485, 102487 to 102508, 102532 to 102573, 102595 to 102642, 102653 to 102694, 102701 to 102718, 102720 to 102734, 102736 to 102757, 102799 to 102836, 102847 to 102882, 102890 to 102927, 102938 to 102971, 102982 to 103019, 103014 to 103027, 103027 to 103054, 103065 to 103088, 103090 to 103108, 103098 to 103112, 103117 to 103138, 103152 to 103170, 103174 to 103204, 103206 to 103234, 103240 to 103268, 103286 to 103325, 103327 to 103347, 103349 to 103384, 103386 to 103405, 103422 to 103449, 103451 to 103493, 103495 to 103509, 103511 to 103560, 103565 to 103582, 103585 to 103607, 103631 to 103645, 103653 to 103684, 103683 to 103696, 103691 to 103733, 103738 to 103762, 103752 to 103765, 103755 to 103768, 103758 to 103771, 103790 to 103814, 103803 to 103816, 103830 to 103865, 103900 to 103923, 103912 to 103933, 103945 to 103964, 103990 to 104005, 104024 to 104055, 104058 to 104077, 104086 to 104099, 104095 to 104122, 104124 to 104146, 104148 to 104168, 104162 to 104176, 104173 to 104187, 104201 to 104241, 104234 to 104266, 104268 to 104286, 104288 to 104302, 104304 to 104335, 104340 to 104354, 104356 to 104373, 104375 to 104391, 104393 to 104417, 104426 to 104439, 104448 to 104478, 104480 to 104504, 104519 to 104546, 104549 to 104580, 104604 to 104620, 104620 to 104646, 104654 to 104673, 104675 to 104691, 104689 to 104776, 104829 to 104842, 104838 to 104852, 104934 to 104952, 104956 to 104987, 104993 to 105045, 105041 to 105055, 105047 to 105078, 105090 to 105107, 105101 to 105115, 105109 to 105137, 105149 to 105167, 105163 to 105176, 105185 to 105237, 105230 to 105243, 105233 to 105250, 105260 to 105286, 105288 to 105340, 105345 to 105370, 105372 to 105402, 105441 to 105458, 105460 to 105521, 105526 to 105541, 105543 to 105560, 105562 to 105575, 105582 to 105606, 105616 to 105671, 105677 to 105704, 105703 to 105725, 105746 to 105759, 105750 to 105765, 105776 to 105796, 105798 to 105824, 105827 to 105907, 105924 to 105939, 105941 to 105963, 105990 to 106014, 106017 to 106048, 106039 to 106072, 106061 to 106074, 106073 to 106102, 106092 to 106107, 106114 to 106159, 106161 to 106180, 106197 to 106243, 106237 to 106250, 106243 to 106256, 106247 to 106267, 106273 to 106333, 106335 to 106367, 106369 to 106417, 106419 to 106471, 106486 to 106523, 106525 to 106538, 106552 to 106572, 106584 to 106598, 106609 to 106696, 106698 to 106723, 106725 to 106740, 106743 to 106781, 106783 to 106811, 106826 to 106866, 106875 to 106902, 106916 to 106935, 106942 to 106960, 106991 to 107010, 107019 to 107038, 107040 to 107072, 107079 to 107094, 107087 to 107101, 107090 to 107109, 107113 to 107127, 107129 to 107143, 107154 to 107172, 107174 to 107198, 107210 to 107226, 107226 to 107239, 107237 to 107274, 107296 to 107356, 107358 to 107381, 107383 to 107415, 107417 to 107433, 107435 to 107455, 107457 to 107508, 107510 to 107525, 107527 to 107546, 107559 to 107573, 107586 to 107617, 107643 to 107689, 107694 to 107716, 107744 to 107792, 107790 to 107832, 107834 to 107860, 107864 to 107896, 107898 to 107912, 107914 to 107953, 107967 to 107992, 107994 to 108008, 108010 to 108038, 108065 to 108084, 108113 to 108215, 108220 to 108249, 108253 to 108281, 108283 to 108304, 108317 to 108359, 108361 to 108375, 108386 to 108402, 108421 to 108440, 108538 to 108551, 108561 to 108575, 108577 to 108616, 108618 to 108665, 108677 to 108707, 108735 to 108768, 108762 to 108777, 108780 to 108824, 108842 to 108885, 108907 to 108970, 108983 to 109019, 109021 to 109053, 109055 to 109068, 109070 to 109099, 109097 to 109122, 109113 to 109132, 109125 to 109165, 109167 to 109181, 109183 to 109200, 109214 to 109248, 109256 to 109277, 109281 to 109298, 109298 to 109311, 109300 to 109318, 109324 to 109374, 109377 to 109397, 109399 to 109437, 109446 to 109461, 109463 to 109476, 109472 to 109485, 109478 to 109514, 109516 to 109540, 109556 to 109588, 109601 to 109644, 109661 to 109681, 109683 to 109709, 109707 to 109737, 109739 to 109754, 109754 to 109768, 109770 to 109798, 109810 to 109829, 109859 to 109877, 109879 to 109934, 109955 to 109975, 109975 to 109988, 109994 to 110096, 110103 to 110129, 110131 to 110152, 110153 to 110173, 110175 to 110195, 110192 to 110226, 110297 to 110312, 110301 to 110314, 110308 to 110333, 110335 to 110351, 110353 to 110368, 110376 to 110401, 110418 to 110462, 110464 to 110481, 110531 to 110558, 110571 to 110590, 110599 to 110639, 110630 to 110643, 110641 to 110661, 110668 to 110681, 110683 to 110709, 110717 to 110798, 110804 to 110849, 110853 to 110890, 110928 to 110966, 110971 to 111003, 111000 to 111013, 111015 to 111033, 111035 to 111050, 111062 to 111094, 111092 to 111105, 111107 to 111140, 111161 to 111203, 111209 to 111223, 111224 to 111280, 111275 to 111290, 111283 to 111303, 111305 to 111320, 111311 to 111347, 111355 to 111368, 111357 to 111371, 111360 to 111381, 111373 to 111421, 111412 to 111426, 111451 to 111468, 111467 to 111480, 111482 to 111496, 111486 to 111500, 111497 to 111510, 111531 to 111564, 111580 to 111606, 111616 to 111637, 111658 to 111671, 111674 to 111688, 111692 to 111710, 111712 to 111725, 111727 to 111761, 111781 to 111804, 111811 to 111828, 111831 to 111849, 111856 to 111871, 111901 to 111917, 111919 to 111940, 111942 to 111987, 111984 to 112002, 112004 to 112069, 112070 to 112091, 112093 to 112116, 112118 to 112132, 112139 to 112170, 112180 to 112196, 112204 to 112223, 112236 to 112283, 112329 to 112343, 112345 to 112383, 112385 to 112401, 112404 to 112423, 112463 to 112477, 112485 to 112547, 112563 to 112581, 112583 to 112597, 112607 to 112638, 112640 to 112664, 112683 to 112721, 112730 to 112759, 112773 to 112811, 112811 to 112825, 112828 to 112862, 112882 to 112912, 112914 to 112967, 112968 to 112982, 112984 to 113016, 113044 to 113064, 113074 to 113097, 113111 to 113153, 113169 to 113194, 113198 to 113212, 113214 to 113230, 113232 to 113263, 113265 to 113284, 113306 to 113328, 113330 to 113355, 113357 to 113371, 113404 to 113422, 113421 to 113489, 113533 to 113559, 113561 to 113574, 113595 to 113616, 113648 to 113700, 113702 to 113739, 113762 to 113823, 113825 to 113960, 113962 to 114015, 114017 to 114048, 114045 to 114124, 114151 to 114170, 114182 to 114218, 114230 to 114270, 114272 to 114292, 114296 to 114339, 114354 to 114433, 114440 to 114457, 114459 to 114484, 114478 to 114536, 114538 to 114559, 114567 to 114592, 114594 to 114610, 114612 to 114652, 114681 to 114752, 114775 to 114805, 114803 to 114816, 114807 to 114821, 114823 to 114847, 114868 to 114912, 114947 to 114961, 114974 to 114997, 115001 to 115015, 115004 to 115017, 115019 to 115069, 115060 to 115073, 115072 to 115085, 115087 to 115100, 115102 to 115124, 115132 to 115151, 115154 to 115168, 115188 to 115208, 115219 to 115256, 115258 to 115283, 115285 to 115300, 115331 to 115353, 115355 to 115372, 115380 to 115397, 115399 to 115412, 115426 to 115475, 115496 to 115510, 115521 to 115545, 115555 to 115580, 115582 to 115600, 115602 to 115621, 115653 to 115677, 115692 to 115720, 115722 to 115738, 115769 to 115783, 115792 to 115808, 115819 to 115837, 115846 to 115878, 115888 to 115901, 115916 to 115932, 115943 to 115956, 115967 to 115993, 115996 to 116014, 116027 to 116045, 116105 to 116127, 116126 to 116139, 116141 to 116158, 116171 to 116186, 116194 to 116208, 116257 to 116279, 116318 to 116373, 116375 to 116437, 116439 to 116454, 116456 to 116496, 116500 to 116532, 116534 to 116554, 116556 to 116573, 116575 to 116592, 116596 to 116615, 116617 to 116650, 116650 to 116664, 116666 to 116694, 116775 to 116792, 116794 to 116811, 116813 to 116838, 116840 to 116872, 116890 to 116911, 116921 to 116948, 116952 to 116988, 116990 to 117006, 117008 to 117036, 117059 to 117133, 117187 to 117207, 117204 to 117217, 117209 to 117237, 117239 to 117252, 117255 to 117275, 117277 to 117300, 117337 to 117371, 117373 to 117416, 117418 to 117450, 117456 to 117507, 117518 to 117532, 117534 to 117590, 117582 to 117604, 117593 to 117617, 117621 to 117648, 117640 to 117662, 117664 to 117688, 117690 to 117711, 117728 to 117743, 117747 to 117781, 117784 to 117801, 117792 to 117822, 117824 to 117842, 117850 to 117869, 117890 to 117940, 117936 to 117968, 117970 to 117990, 117989 to 118034, 118034 to 118057, 118061 to 118083, 118086 to 118122, 118122 to 118182, 118172 to 118186, 118197 to 118211, 118216 to 118275, 118291 to 118316, 118318 to 118354, 118373 to 118388, 118391 to 118405, 118407 to 118423, 118425 to 118456, 118465 to 118492, 118498 to 118521, 118533 to 118551, 118553 to 118581, 118587 to 118617, 118620 to 118679, 118687 to 118716, 118731 to 118771, 118779 to 118805, 118816 to 118830, 118832 to 118895, 118910 to 119065, 119067 to 119081, 119095 to 119140, 119170 to 119205, 119210 to 119232, 119230 to 119246, 119236 to 119252, 119255 to 119274, 119271 to 119284, 119290 to 119307, 119320 to 119335, 119357 to 119463, 119465 to 119483, 119485 to 119535, 119550 to 119571, 119577 to 119608, 119610 to 119646, 119648 to 119688, 119713 to 119752, 119743 to 119784, 119786 to 119800, 119822 to 119836, 119830 to 119847, 119849 to 119900, 119912 to 119925, 119960 to 119982, 119984 to 120013, 120038 to 120054, 120057 to 120090, 120092 to 120134, 120138 to 120154, 120157 to 120189, 120187 to 120200, 120191 to 120211, 120225 to 120239, 120242 to 120267, 120271 to 120301, 120320 to 120340, 120363 to 120406, 120406 to 120421, 120414 to 120468, 120457 to 120470, 120487 to 120518, 120545 to 120563, 120567 to 120587, 120589 to 120625, 120619 to 120633, 120650 to 120663, 120676 to 120694, 120703 to 120717, 120721 to 120737, 120755 to 120812, 120816 to 120838, 120843 to 120871, 120873 to 120899, 120903 to 120922, 120933 to 120946, 120936 to 120981, 120983 to 121004, 121006 to 121021, 121023 to 121036, 121035 to 121061, 121063 to 121079, 121081 to 121097, 121105 to 121134, 121138 to 121156, 121155 to 121168, 121158 to 121174, 121166 to 121189, 121194 to 121208, 121201 to 121218, 121213 to 121237, 121246 to 121271, 121298 to 121314, 121311 to 121324, 121327 to 121351, 121359 to 121388, 121390 to 121419, 121446 to 121462, 121468 to 121487, 121499 to 121515, 121517 to 121543, 121545 to 121564, 121575 to 121597, 121599 to 121617, 121619 to 121662, 121664 to 121681, 121683 to 121700, 121702 to 121751, 121773 to 121788, 121790 to 121805, 121807 to 121834, 121836 to 121857, 121859 to 121874, 121877 to 121925, 121923 to 121936, 121928 to 121943, 121962 to 121976, 121978 to 121992, 122004 to 122028, 122030 to 122056, 122046 to 122059, 122052 to 122072, 122080 to 122095, 122099 to 122122, 122143 to 122163, 122169 to 122189, 122258 to 122274, 122289 to 122309, 122311 to 122346, 122357 to 122395, 122446 to 122468, 122471 to 122489, 122491 to 122512, 122526 to 122541, 122543 to 122557, 122579 to 122592, 122606 to 122653, 122663 to 122690, 122728 to 122742, 122757 to 122770, 122779 to 122840, 122842 to 122857, 122900 to 122923, 122933 to 122955, 122968 to 123042, 123055 to 123076, 123094 to 123108, 123114 to 123134, 123143 to 123160, 123162 to 123180, 123184 to 123198, 123200 to 123235, 123237 to 123321, 123314 to 123329, 123342 to 123360, 123356 to 123389, 123391 to 123410, 123412 to 123453, 123455 to 123485, 123488 to 123503, 123506 to 123524, 123526 to 123543, 123545 to 123578, 123598 to 123634, 123654 to 123683, 123685 to 123706, 123710 to 123774, 123803 to 123816, 123818 to 123831, 123896 to 123939, 123941 to 123974, 123976 to 124021, 124026 to 124040, 124042 to 124079, 124091 to 124109, 124158 to 124185, 124238 to 124274, 124319 to 124332, 124335 to 124373, 124394 to 124412, 124419 to 124445, 124450 to 124470, 124472 to 124493, 124499 to 124520, 124522 to 124561, 124564 to 124595, 124607 to 124649, 124662 to 124729, 124750 to 124767, 124769 to 124793, 124812 to 124828, 124853 to 124906, 124923 to 124948, 124958 to 124986, 125023 to 125042, 125032 to 125046, 125065 to 125083, 125073 to 125091, 125093 to 125107, 125132 to 125149, 125139 to 125154, 125151 to 125200, 125201 to 125274, 125314 to 125329, 125331 to 125370, 125372 to 125386, 125411 to 125431, 125433 to 125462, 125475 to 125562, 125564 to 125589, 125605 to 125639, 125641 to 125699, 125719 to 125732, 125737 to 125769, 125815 to 125829, 125834 to 125848, 125850 to 125884, 125899 to 125966, 125967 to 125999, 126026 to 126080, 126097 to 126115, 126130 to 126149, 126151 to 126179, 126186 to 126238, 126241 to 126279, 126275 to 126295, 126297 to 126312, 126320 to 126363, 126376 to 126395, 126406 to 126419, 126420 to 126442, 126467 to 126501, 126503 to 126538, 126566 to 126580, 126584 to 126597, 126620 to 126653, 126654 to 126694, 126697 to 126715, 126764 to 126777, 126792 to 126828, 126842 to 126862, 126866 to 126879, 126881 to 126897, 126906 to 126925, 126956 to 126987, 126989 to 127023, 127026 to 127135, 127142 to 127174, 127176 to 127191, 127193 to 127217, 127229 to 127253, 127255 to 127280, 127294 to 127394, 127396 to 127415, 127417 to 127478, 127491 to 127504, 127506 to 127530, 127542 to 127566, 127582 to 127628, 127654 to 127675, 127681 to 127706, 127706 to 127739, 127769 to 127792, 127808 to 127829, 127839 to 127888, 127900 to 127932, 127943 to 127975, 127988 to 128046, 128048 to 128069, 128068 to 128106, 128105 to 128118, 128121 to 128157, 128159 to 128188, 128190 to 128268, 128279 to 128317, 128321 to 128335, 128342 to 128368, 128374 to 128446, 128444 to 128540, 128546 to 128586, 128588 to 128640, 128642 to 128674, 128675 to 128879, 128881 to 128936, 128934 to 129000, 129002 to 129060, 129074 to 129100, 129107 to 129123, 129125 to 129163, 129168 to 129230, 129264 to 129277, 129284 to 129318, 129320 to 129346, 129357 to 129391, 129393 to 129420, 129447 to 129485, 129489 to 129504, 129514 to 129540, 129550 to 129563, 129559 to 129595, 129606 to 129627, 129633 to 129681, 129683 to 129697, 129699 to 129716, 129706 to 129738, 129757 to 129790, 129792 to 129820, 129812 to 129846, 129851 to 129867, 129869 to 129883, 129885 to 129915, 129917 to 129955, 129957 to 130046, 130042 to 130070, 130110 to 130156, 130158 to 130309, 130311 to 130373, 130375 to 130391, 130407 to 130429, 130439 to 130461, 130475 to 130507, 130512 to 130550, 130552 to 130582, 130584 to 130614, 130616 to 130764, 130766 to 130869, 130871 to 131021, 131033 to 131051, 131092 to 131105, 131112 to 131188, 131194 to 131237, 131233 to 131247, 131236 to 131287, 131292 to 131307, 131314 to 131333, 131373 to 131386, 131396 to 131417, 131419 to 131439, 131429 to 131458, 131481 to 131499, 131676 to 131689, 131729 to 131743, 131745 to 131764, 131785 to 131807, 131809 to 131875, 131877 to 131953, 131955 to 131980, 132020 to 132068, 132086 to 132108, 132118 to 132138, 132152 to 132183, 132185 to 132205, 132219 to 132232, 132234 to 132252, 132261 to 132291, 132319 to 132337, 132345 to 132363, 132365 to 132378, 132414 to 132483, 132504 to 132547, 132549 to 132582, 132584 to 132602, 132616 to 132642, 132643 to 132681, 132685 to 132714, 132736 to 132769, 132771 to 132793, 132809 to 132825, 132827 to 132841, 132861 to 132884, 132882 to 132900, 132899 to 132915, 132917 to 132951, 132940 to 132954, 132958 to 132983, 132985 to 133031, 133032 to 133051, 133042 to 133060, 133051 to 133071, 133073 to 133087, 133083 to 133104, 133097 to 133110, 133131 to 133199, 133198 to 133222, 133233 to 133249, 133251 to 133284, 133327 to 133429, 133431 to 133596, 133588 to 133602, 133598 to 133611, 133613 to 133628, 133628 to 133646, 133651 to 133670, 133666 to 133707, 133718 to 133742, 133743 to 133777, 133779 to 133794, 133821 to 133851, 133859 to 133880, 133890 to 133921, 133923 to 133974, 133982 to 133998, 134000 to 134036, 134065 to 134107, 134120 to 134173, 134165 to 134179, 134187 to 134200, 134207 to 134242, 134244 to 134258, 134260 to 134273, 134275 to 134299, 134314 to 134346, 134356 to 134371, 134365 to 134380, 134374 to 134420, 134445 to 134477, 134508 to 134523, 134531 to 134548, 134542 to 134555, 134568 to 134621, 134647 to 134667, 134679 to 134719, 134721 to 134824, 134826 to 134849, 134856 to 134869, 134877 to 134910, 134912 to 134966, 134960 to 134980, 134989 to 135012, 135014 to 135066, 135074 to 135093, 135108 to 135125, 135151 to 135260, 135264 to 135277, 135273 to 135310, 135321 to 135337, 135340 to 135365, 135360 to 135374, 135364 to 135386, 135388 to 135430, 135432 to 135447, 135498 to 135521, 135519 to 135545, 135559 to 135622, 135624 to 135647, 135656 to 135673, 135675 to 135704, 135721 to 135742, 135753 to 135796, 135815 to 135858, 135860 to 135880, 135883 to 135915, 135922 to 135965, 135979 to 135993, 135995 to 136036, 136051 to 136065, 136108 to 136165, 136173 to 136190, 136192 to 136287, 136289 to 136303, 136317 to 136346, 136375 to 136415, 136429 to 136470, 136472 to 136496, 136498 to 136532, 136542 to 136565, 136643 to 136657, 136674 to 136701, 136704 to 136719, 136715 to 136728, 136721 to 136737, 136737 to 136750, 136783 to 136810, 136824 to 136849, 136859 to 136896, 136898 to 136927, 136949 to 136983, 136985 to 137000, 137053 to 137071, 137077 to 137097, 137108 to 137164, 137166 to 137196, 137198 to 137221, 137223 to 137267, 137276 to 137359, 137360 to 137385, 137393 to 137440, 137438 to 137496, 137498 to 137518, 137523 to 137536, 137539 to 137572, 137584 to 137612, 137614 to 137628, 137630 to 137644, 137646 to 137669, 137702 to 137727, 137731 to 137745, 137759 to 137772, 137784 to 137819, 137832 to 137858, 137861 to 137876, 137878 to 137900, 137909 to 137925, 137924 to 137961, 137968 to 137981, 138011 to 138033, 138035 to 138077, 138079 to 138097, 138224 to 138238, 138232 to 138252, 138242 to 138256, 138255 to 138284, 138295 to 138326, 138328 to 138357, 138359 to 138389, 138403 to 138449, 138451 to 138492, 138500 to 138515, 138524 to 138548, 138555 to 138568, 138571 to 138589, 138589 to 138629, 138644 to 138680, 138697 to 138710, 138712 to 138729, 138744 to 138761, 138776 to 138801, 138860 to 138896, 138898 to 138923, 138925 to 138965, 138967 to 139008, 139010 to 139031, 139029 to 139043, 139034 to 139048, 139041 to 139056, 139055 to 139074, 139078 to 139094, 139084 to 139098, 139092 to 139116, 139133 to 139147, 139154 to 139173, 139175 to 139192, 139204 to 139229, 139231 to 139255, 139257 to 139270, 139272 to 139303, 139315 to 139335, 139337 to 139372, 139383 to 139397, 139399 to 139419, 139423 to 139437, 139435 to 139492, 139501 to 139518, 139508 to 139521, 139571 to 139586, 139588 to 139622, 139636 to 139655, 139657 to 139673, 139685 to 139699, 139724 to 139795, 139796 to 139811, 139818 to 139834, 139836 to 139857, 139856 to 139869, 139859 to 139882, 139891 to 139920, 139930 to 139952, 139965 to 139980, 139982 to 140011, 140013 to 140031, 140047 to 140072, 140074 to 140099, 140101 to 140119, 140121 to 140135, 140144 to 140158, 140157 to 140183, 140185 to 140210, 140231 to 140262, 140258 to 140272, 140264 to 140288, 140290 to 140325, 140339 to 140364, 140369 to 140402, 140428 to 140451, 140453 to 140510, 140512 to 140541, 140556 to 140621, 140626 to 140651, 140653 to 140724, 140726 to 140789, 140802 to 140825, 140837 to 140861, 140863 to 140896, 140903 to 140927, 140958 to 140993, 141001 to 141014, 141022 to 141053, 225 to 238, 1163-1178, 2526-2539, 2805-2820, 3027-3040, 3208-3222, 3212-3225, 3228-3241, 3243-3256, 3810-3854, 4664-4680, 5516-5529, 5657-5671, 5661-5676, 5964-5977, 6217-6234, 6224-6237, 6408-6422, 7300-7313, 7399-7412, 7541-7564, 7626-7640, 7662-7694, 7791-7806, 7853-7868, 8206-8219, 8443-8456, 8739-8752, 9197-9212, 10189-10203, 10754-10768, 10758-10771, 11790-11803, 11870-11883, 11993-12007, B11996-12011, 12017-12040, 12095-12108, 12345-12358, 12721-12734, 13372-13386, 13489-13505, 15576-15590, 15617-15632, 15840-15853, 16041-16054, 16207-16222, 16308-16321, 16349-16362, 16463-16479, 16528-16542, 16543-16556, 20495-20508, 20617-20630, 20960-20977, 21465-21479, 21491-21508, 23479-23496, 23741-23755, 25236-25249, 25323-25336, 25447-25462, 25588-25601, 25853-25867, 25885-25898, 26280-26293, 26388-26404, 26416-26450, 26687-26702, 26706-26719, 26783-26796, 27039-27052, 27251-27265, 28683-28698, 29302-29315, 29304-29317, 29308-29321, 29532-29545, 29974-29987, 30054-30068, 30267-30281, 30623-30638, 30628-30641, 30814-30827, 30881-30894, 32459-32478, 37299-37315, 39083-39096, 39370-39383, 39659-39672, 40814-40831, 40851-40864, 41782-41795, 41873-41886, 42037-42050, 42048-42063, 42096-42116, 42959-42973, 43165-43178, 45926-45939, 48163-48176, 52732-52745, 52984-53015, 54404-54420, 55294-55320, 55337-55350, 55420-55434, 55487-55501, 55623-55638, 56195-56214, 56584-56597, 57267-57282, 58126-58139, 58170-58183, 58295-58309, 58658-58671, 58906-58921, 58988-59005, 59024-59045, 59191-59207, 59236-59251, 59298-59312, 59358-59378, 59400-59413, 59434-59447, 59589-59602, 59620-59642, 59718-59743, 59826-59841, 59843-59864, 59882-59906, 59930-59958, 59959-60004, 60006-60029, 60033-60071, 60139-60171, 60193-60215, 60212-60225, 60231-60244, 60246-60265, 60267-60282, 60292-60309, 60348-60361, 60358-60429, 60427-60517, 60519-60545, 60557-60575, 60580-60593, 60595-60622, 60675-60690, 60697-60713, 60727-60754, 60756-60799, 60801-60817, 60819-60855, 61423-61436, 61592-61605, 61624-61637, 61673-61713, 61715-61731, 61733-61752, 61769-61794, 61805-61825, 62101-62114, 62302-62315, 62436-62449, 62664-62679, 62993-63006, 63098-63111, 63347-63367, 63371-63396, 63385-63398, 63526-63539, 65032-65045, 66556-66569, 67158-67183, 67181-67194, 68007-68021, 68644-68657, 69294-69317, 69306-69323, 69353-69366, 70497-70511, 71600-71613, 71887-71905, 72259-72272, 72589-72602, 72783-72796, 73528-73541, 73783-73800, 74907-74920, 75965-75981, 75983-75998, 76004-76020, 76110-76166, 76186-76205, 76234-76253, 76261-76280, 76369-76382, 77139-77152, 77409-77422, 77478-77524, 77526-77590, 77628-77641, 77688-77701, 78275-78308, 78310-78332, 78340-78356, 78358-78371, 78373-78395, 78397-78440, 78442-78455, 78475-78489, 78696-78709, 78847-78860, 79493-79516, 79705-79718, 81009-81054, 81353-81367, 81970-81986, 81991-82006, 82042-82106, 82278-82291, 82716-82735, 84314-84328, 85628-85665, 86226-86239, 86237-86253, 86566-86579, 86945-86959, 87337-87358, 87662-87675, 89424-89439, 89972-89985, 90782-90795, 90939-90953, 90942-90955, 90965-90981, 91101-91115, 92083-92096, 92164-92177, 92179-92192, 92194-92210, 92212-92236, 92245-92260, 92262-92302, 92304-92321, 92323-92366, 92375-92389, 92392-92405, 92407-92426, 92442-92459, 92497-92516, 92578-92591, 92599-92612, 92614-92651, 92659-92684, 92686-92699, 92704-92726, 92731-92750, 92752-92774, 92780-92795, 92800-92813, 92839-92858, 92860-92891, 92893-92906, 92908-92921, 92923-92941, 92965-92986, 92988-93002, 93044-93059, 93061-93076, 93105-93122, 93142-93209, 93227-93241, 93288-93305, 93325-93344, 93398-93412, 93572-93586, 94509-94522, 95720-95738, 97050-97065, 97079-97098, 97127-97194, 97208-97230, 97232-97284, 97286-97311, 97313-97362, 97368-97383, 97426-97439, 98077-98090, 98227-98240, 98232-98255, 99151-99164, 99405-99418, 99570-99583, 99733-99748, 101829-101842, 101882-101895, 101955-101968, 102202-102215, 103310-103325, 103653-103666, 103908-103923, 103912-103928, 103917-103933, 104971-104984, 105217-105230, 105233-105250, 105443-105457, 105544-105559, 106047-106071, 106061-106074, 106093-106107, 106114-106130, 106243-106256, 106251-106264, 106840-106855, 108113-108130, 108325-108338, 108856-108869, 109109-109122, 109113-109127, 109116-109132, 110301-110314, 110315-110328, 110317-110330, 112528-112546, 112607-112620, 114775-114788, 116322-116335, 116968-116981, 117788-117801, 118034-118057, 118230-118246, 118235-118248, 118870-118883, 119755-119784, 119786-119800, 120363-120406, 120504-120517, 121161-121174, 121330-121347, 121338-121351, 123417-123430, 123464-123481, 125026-125042, 127046-127071, 127090-127103, 127311-127324, 127354-127367, 127363-127379, 127399-127412, 127863-127876, 128134-128148, 128280-128310, 128343-128368, 128444-128457, 128446-128469, 128498-128511, 128511-128524, 129892-129905, 130261-130283, 130375-130388, 130415-130428, 130634-130650, 130667-130717, 130719-130764, 130783-130796, 130798-130820, 130840-130861, 130975-130994, 131112-131132, 131142-131161, 131233-131246, 131729-131743, 132754-132767, 132924-132937, 133174-133190, 133198-133212, 133207-133222, 133476-133489, 133479-133492, 133491-133531, 133533-133550, 133555-133594, 134160-134173, 134165-134178, 134533-134546, 136724-136737, 137438-137463, 137878-137891, 138082-138097, 138233-138252, 138930-138943, 138947-138960, 138950-138963, 139502-139518, 139508-139521, and 140978-140991 of SEQ ID NO: 1.

5. The oligonucleotide of claim 1, wherein the oligonucleotide comprises or consists of either 17 to 22 nucleotides in length or 15 to 20 nucleotides in length.

6. The oligonucleotide of claim 1, wherein the oligonucleotide consists of 20 nucleotides in length.

7. The oligonucleotide of claim 1, wherein 5-methyl cytosine is used in place of cytosine in the oligonucleotide.

8. The oligonucleotide of claim 1, wherein the one or more modified nucleosides is a 2′ sugar modified nucleoside.

9. The oligonucleotide of claim 8, wherein each of the one or more 2′ sugar modified nucleoside is a 2′-O-alkyl-RNA nucleoside, a 2′-O-methyl-RNA nucleoside, a 2′-alkoxy-RNA nucleoside, a 2′-O-methoxyethyl-RNA nucleoside, a 2′-amino-DNA nucleoside, a 2′-fluoro-DNA nucleoside, an arabino nucleic acid (ANA) nucleoside, a 2′-fluoro-ANA nucleoside, or a LNA nucleoside.

10. The oligonucleotide of claim 1, wherein the one or more modified nucleoside is a 2′-O-methoxyethyl-RNA nucleoside.

11. The oligonucleotide of claim 1, wherein the oligonucleotide comprises at least one modified internucleoside linkage.

12. The oligonucleotide of claim 11, wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage.

13. The oligonucleotide of claim 12, wherein at least 60% of the internucleoside linkages in the oligonucleotide are phosphorothioate internucleoside linkages.

14. The oligonucleotide of claim 1, wherein the oligonucleotide is capable of recruiting RNase H.

15. The oligonucleotide of claim 14, wherein the oligonucleotide is a gapmer.

16. The oligonucleotide of claim 14, wherein the oligonucleotide is a gapmer of formula 5′-F-G-F′-3′, where region F and F′ independently comprise 1 to 7 modified nucleosides and G is a region comprising between 6 and 16 nucleosides which are capable of recruiting RNaseH.

17. The oligonucleotide of claim 16, wherein the modified nucleosides are 2′ sugar modified nucleosides, wherein each of the 2′ sugar modified nucleosides is a 2′-O-alkyl-RNA nucleoside, a 2′-O-methyl-RNA nucleoside, a 2′-alkoxy-RNA nucleoside, a 2′-O-methoxyethyl-RNA nucleoside, a 2′-amino-DNA nucleoside, a 2′-fluoro-DNA nucleoside, an arabino nucleic acid (ANA) nucleoside, a 2′-fluoro-ANA nucleoside, or a LNA nucleoside.

18. The oligonucleotide of claim 1, wherein the oligonucleotide is a gapmer of the formula F-G-F′ wherein each of regions F and F′ independently consists of 2, 3, 4, or 5 modified nucleoside units and region G consists of 9, 10, 11, 12, 13, 14, or 15 nucleoside units.

19. The oligonucleotide of claim 1, wherein the oligonucleotide is a gapmer of the formula F-G-F′ wherein each of regions F and F′ independently consists of 2, 3, 4, or 5 2′—O-methoxyethyl-ribose sugar (2′-MOE) units, and region G consists of 9, 10, 11, 12, 13, 14, or 15 DNA units.

20. The oligonucleotide of claim 16, wherein each of regions F and F′ independently consists of 5 2′—O-methoxyethyl-ribose sugar (2′-MOE) nucleoside units and region G consists of 10 DNA nucleoside units.

21. An antisense oligonucleotide for inducing human paternal ubiquitin-protein ligase E3A (UBE3A) expression, wherein the antisense oligonucleotide comprises a contiguous nucleotide sequence that is 100% complementary to a region of the target nucleic acid of position 1 to 55318 of SEQ ID NO: 1, wherein the oligonucleotide is either 15 to 20 nucleotides in length or 17 to 22 nucleotides in length, wherein the oligonucleotide comprises one or more modified nucleosides, wherein the one or more modified nucleosides is a 2′ sugar modified nucleoside, wherein each of the 2′ sugar modified nucleosides is a 2′-O-alkyl-RNA nucleoside, a 2′-O-methyl-RNA nucleoside, a 2′-alkoxy-RNA nucleoside, a 2′-O-methoxyethyl-RNA nucleoside, a 2′-amino-DNA nucleoside, a 2′-fluoro-DNA nucleoside, an arabino A nucleic acid (ANA) nucleoside, a 2′-fluoro-ANA nucleoside, or a LNA nucleoside, wherein the oligonucleotide comprises at least one modified internucleoside linkage, wherein the modified internucleoside linkage is a phosphorothioate linkage, wherein the oligonucleotide is a gapmer of the formula F-G-F′, wherein each of regions F and F′ independently consists of 2, 3, 4, or 5 modified nucleoside units and region G consists of 9, 10, 11, 12, 13, 14, or 15 nucleoside units.

22. The oligonucleotide of claim 1, wherein the oligonucleotide is in the form of a pharmaceutically acceptable salt.

23. The oligonucleotide of claim 22, wherein the oligonucleotide is in the form of a pharmaceutically acceptable sodium salt.

24. The oligonucleotide of claim 22, wherein the oligonucleotide is in the form of a pharmaceutically acceptable potassium salt.

25. A conjugate comprising the oligonucleotide of claim 1 and at least one conjugate moiety covalently attached to the oligonucleotide.

26. A pharmaceutical composition comprising the oligonucleotide of claim 1, and a pharmaceutically acceptable diluent, solvent, carrier, salt, and/or adjuvant.

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Patent History
Patent number: 12259380
Type: Grant
Filed: Feb 22, 2023
Date of Patent: Mar 25, 2025
Patent Publication Number: 20230296587
Assignee: Hoffmann-La Roche Inc. (Little Falls, NJ)
Inventors: Veronica Costa (Basel), Maj Hedtjärn (Hørsholm), Marius Hoener (Basel), Ravi Jagasia (Basel), Mads Aaboe Jensen (Hørsholm), Christoph Patsch (Basel), Lykke Pedersen (Hørsholm), Søren Vestergaard Rasmussen (Hørsholm)
Primary Examiner: Terra C Gibbs
Application Number: 18/172,707
Classifications
International Classification: C12N 15/11 (20060101); C12N 5/00 (20060101); C12N 5/074 (20100101); C12N 5/0793 (20100101); C12N 5/0797 (20100101); C12N 15/113 (20100101); G01N 33/50 (20060101);